Novel tricyclic compounds

ABSTRACT

The invention provides compounds of Formula (I) and Formula (II) 
     
       
         
         
             
             
         
       
     
     pharmaceutically acceptable salts, pro-drugs, biologically active metabolites, stereoisomers and isomers thereof wherein the variable are defined herein. The compounds of the invention are useful for treating immunological and oncological conditions.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of U.S. Utility applicationSer. No. 12/481,028 filed on Jun. 9, 2009, which claims priority to U.S.Provisional Application Ser. No. 61/131,599 filed on Jun. 10, 2008, U.S.Provisional Application Ser. No. 61/131,602 filed on Jun. 10, 2008, U.S.Provisional Application Ser. No. 61/190,159 filed on Aug. 26, 2008 andU.S. Provisional Application Ser. No. 61/201,064 filed Dec. 5, 2008, thecontents of which are incorporated herein. This application also claimspriority to U.S. Provisional Application Ser. No. 61/265,563 filed onDec. 1, 2009, and U.S. Provisional Application Ser. No. 61/364,116 filedJul. 14, 2010, the contents of which are incorporated herein.

BACKGROUND OF THE INVENTION

The invention provides a novel class of compounds, pharmaceuticalcompositions comprising such compounds and methods of using suchcompounds to treat or prevent diseases or disorders associated withabnormal or deregulated kinase activity, particularly diseases ordisorders that involve abnormal activation of the Jak1, Jak2, Jak3,Tyk2, KDR, Flt-3, CDK2, CDK4, TANK, Trk, FAK, Abl, Bcr-Abl, cMet, b-RAF,FGFR3, c-kit, PDGF-R, Syk, BTK, CSF1R, PKC kinases or Aurora kinases.

The protein kinases represent a large family of proteins that play acentral role in the regulation of a wide variety of cellular processesand maintenance of cellular function. A partial, non-limiting, list ofthese kinases include: non-receptor tyrosine kinases such as the Januskinase family (Jak1, Jak2, Jak3 and Tyk2); the fusion kinases, such asBCR-Abl, focal adhesion kinase (FAK), Fes, Lck and Syk; receptortyrosine kinases such as platelet-derived growth factor receptor kinase(PDGF-R), the receptor kinase for stem cell factor, c-kit, thehepatocyte growth factor receptor, c-Met, and the fibroblast growthfactor receptor, FGFR3; and serine/threonine kinases such as b-RAF,mitogen-activated protein kinases (e.g., MKK6) and SAPK2β. Aberrantkinase activity has been observed in many disease states includingbenign and malignant proliferative disorders as well as diseasesresulting from inappropriate activation of the immune and nervoussystems. The novel compounds of this invention inhibit the activity ofone or more protein kinases and are, therefore, expected to be useful inthe treatment of kinase-mediated diseases.

SUMMARY OF THE INVENTION

In a first embodiment the invention provides a compound of Formula (I)

pharmaceutically acceptable salts, pro-drugs, biologically activemetabolites, stereoisomers and isomers thereof wherein

T is N, U is N, X is CR³ and Y is N; or

T is CR⁶, U is N, X is CR³ and Y is N; or

T is N, U is CR⁴, X is CR³ and Y is N; or

T is CR⁶, U is CR⁴, X is CR³ and Y is N; or

T is CR⁶, U is N, X is NR³ and Y is C; or

T is O, U is N, X is CR³ and Y is C; or

T is NR⁶, U is N, X is CR³ and Y is C; or

T is CR⁶, U is CR⁴, X is NR³ and Y is C; or

T is S, U is N, X is CR³ and Y is C; or

T is N, U is CR⁴, X is NR³ and Y is C; or

T is N, U is N, X is NR³ and Y is C;

R¹, R² and R⁵ are each independently hydrogen, deuterium,—N(R^(a))(R^(b)), halogen, —OR^(a), —SR^(a), —S(O)R^(a), —S(O)₂R^(a),—NO₂, —C(O)OR^(a), —CN, —C(O)N(R^(a))(R^(b)), —N(R^(a))C(O)(R^(b)),—C(O)R^(a), —C(OH)R^(a)R^(b), —N(R^(a))S(O)₂—R^(b),—S(O)₂N(R^(a))(R^(b)), —CF₃, —OCF₃, optionally substituted (C₁-C₆)alkyl,optionally substituted (C₂-C₆)alkenyl, optionally substituted(C₂-C₆)alkynyl, optionally substituted (C₃-C₁₀)cycloalkyl, optionallysubstituted (C₁-C₁₀)heteroaryl, optionally substituted (C₁-C₁₀)heterocyclyl, or optionally substituted (C₆-C₁₀)aryl;

-   -   wherein in a moiety containing —N(R^(a))(R^(b)), the nitrogen,        R^(a) and R^(b) may form a ring such that —N(R^(a))(R^(b))        represents an optionally substituted (C₂-C₁₀)heterocyclyl or        optionally substituted (C₁-C₁₀)heteroaryl linked through a        nitrogen;

R³ is hydrogen, an optionally substituted bridged (C₅-C₁₂)cycloalkyl,optionally substituted bridged (C₂-C₁₀)heterocyclyl, optionallysubstituted (C₁-C₈)alkyl, optionally substituted (C₃-C₁₀)cycloalkyl,optionally substituted (C₃-C₈)cycloalkenyl, optionally substituted(C₆-C₁₀)aryl, optionally substituted (C₁-C₁₀)heteroaryl, optionallysubstituted (C₂-C₁₀)heterocyclyl; or

R³ is -A-D-E-G, wherein:

A is a bond, —C(O)—, optionally substituted (C₁-C₆)alkylene, optionallysubstituted (C₂-C₆)alkenylene, optionally substituted (C₂-C₆)alkynylene,optionally substituted (C₃-C₁₂)cycloalkylene, optionally substituted(C₂-C₆)heterocyclylene, —C(O)N(R^(a))—R^(e)—, —N(R^(a))C(O)—R^(e)—,—O—R^(e)—, —N(R^(a))—R^(e)—, —S—R^(e)—, —S(O)₂—R^(e)—, —S(O)R^(e)—,—C(O—R^(a))(R^(b))—R^(e)—, —S(O)₂N(R^(a))—R^(e)—, —N(R^(a))S(O)₂—R^(e)—or —N(R^(a))C(O)N(R^(b))—R^(e)—;

D is an optionally substituted (C₁-C₈)alkylene, optionally substitutedbridged (C₅-C₁₂)cycloalkylene, optionally substituted(C₃-C₁₀)cycloalkylene, optionally substituted bridged(C₅-C₁₀)cycloalkenylene, optionally substituted (C₃-C₁₀)cycloalkenylene,optionally substituted (C₆-C₁₀)arylene, optionally substituted(C₁-C₁₀)heteroarylene, optionally substituted bridged(C₂-C₁₀)heterocyclylene or an optionally substituted(C₂-C₁₀)heterocyclylene;

E is a bond, —R^(e)—, —R^(e)—C(═NCN)—R^(e)—, —R^(e)—C(O)—R^(e)—,—R^(e)—C(O)C(O)—R^(e)—, —R^(e)—C(O)O—R^(e)—,—R^(e)—C(O)C(O)N(R^(a))—R^(e)—, —R^(e)—N(R^(a))—C(O)C(O)—R^(e)—,—R^(e)—O—R^(e)—, —R^(e)—S(O)₂—R^(e)—, —R^(e)—S(O)—R^(e)—,—R^(e)—S—R^(e)—, —R^(e)—N(R^(a))—R^(e)—, ═N—R^(e)—,—R^(e)—N(R^(a))C(O)—R^(e)—, —R^(e)C(O)N(R^(a))R^(e)—,—R^(e)—OC(O)N(R^(a))—R^(e)—, —R^(e)—N(R^(a))C(O)OR^(e)—,—R^(e)—OC(O)—R^(e), —R^(e)—OC(O)—O—R^(e),—R^(e)—N(R^(a))C(O)N(R^(b))—R^(e)—, —R^(e)—N(R^(a))S(O)₂—R^(e)—,—R^(e)—S(O)₂N(R^(a))—R^(e)—, or —R^(e)—N(R^(a))S(O)₂N(R^(a))—R^(e)—; or

E is

where in all cases, E is linked to either a carbon or a nitrogen atom inD;

G is hydrogen, deuterium, —N(R^(a))(R^(b)), halogen, —OR^(a), —SR^(a),—S(O)R^(a), —S(O)₂R^(a), —NO₂, —C(O)OR^(a), —CN, —C(O)N(R^(a))(R^(b)),—N(R^(a))C(O)R^(b), —N(R^(a))C(O)OR^(b), —OC(O)N(R^(a)),—N(R^(a))C(O)N(R^(b))₂, —C(O—R^(a))(R^(b))₂, —C(O)R^(a), —CF₃, —OCF₃,—N(R^(a))S(O)₂R^(b), —S(O)₂N(R^(a))(R^(b)), —S(O)₂N(R^(a))C(O)R^(b), anoptionally substituted —(C₁-C₆)alkyl, an optionally substituted—(C₂-C₆)alkenyl, an optionally substituted —(C₂-C₆)alkynyl, anoptionally substituted —(C₃-C₁₀)cycloalkyl, an optionally substituted—(C₁-C₁₀)heteroaryl, an optionally substituted —(C₁-C₁₀) heterocyclyl,an optionally substituted —(C₆-C₁₀)aryl;

-   -   wherein in a moiety containing —N(R^(a))(R^(b)), the nitrogen,        R^(a) and R^(b) may form a ring such that —N(R^(a))(R^(b))        represents an optionally substituted (C₂-C₁₀)heterocyclyl or an        optionally substituted (C₁-C₁₀) heteroaryl linked through a        nitrogen;

R⁴ and R⁶ are each independently a hydrogen, halogen, deuterium, CF₃,CHF₂, CH₂F, CH₂CF₃, C(O)OH, C(O)OCH₃, CN, an optionally substitutedbridged (C₅-C₁₂)cycloalkyl group, optionally substituted bridged(C₂-C₁₀)heterocyclyl group, optionally substituted (C₁-C₈)alkyl,optionally substituted (C₃-C₁₀)cycloalkyl, optionally substituted(C₃-C₈)cycloalkenyl, optionally substituted (C₆-C₁₀)aryl, optionallysubstituted (C₁-C₁₀)heteroaryl, optionally substituted(C₂-C₁₀)heterocyclyl or -J-L-M-Q;

wherein:

J is a bond, —C(O)—, optionally substituted (C₁-C₆)alkylene, optionallysubstituted (C₂-C₆)alkenylene, optionally substituted (C₂-C₆)alkynylene,optionally substituted (C₃-C₁₂)cycloalkylene, optionally substituted(C₂-C₆)heterocyclylene, —C(O)N(R^(a))—R^(e)—, —N(R^(a))C(O)—R^(e)—,—O—R^(e)—, —N(R^(a))—R^(e)—, —S—R^(e)—, —S(O)₂—R^(e)—, —S(O)R^(e)—,—C(O—R^(a))(R^(b))—R^(e)—, —S(O)₂N(R^(a))—R^(e)—, —N(R^(a))S(O)₂—R^(e)—or —N(R^(a))C(O)N(R^(b))—R^(e)—;

L is a bond, an optionally substituted (C₁-C₈)alkylene, optionallysubstituted bridged (C₅-C₁₂)cycloalkylene, optionally substituted(C₃-C₁₀)cycloalkylene, optionally substituted bridged(C₅-C₁₀)cycloalkenylene, optionally substituted (C₃-C₁₀)cycloalkenylene,optionally substituted (C₆-C₁₀)arylene, optionally substituted(C₁-C₁₀)heteroarylene, optionally substituted bridged(C₂-C₁₀)heterocyclylene or an optionally substituted(C₂-C₁₀)heterocyclylene;

M is a bond, —R^(e)—, —R^(e)—C(O)—R^(e)—, —R^(e)—C(O)C(O)—R^(e)—,—R^(e)—C(O)O—R^(e)—, —R^(e)—OC(O)—R^(e), —R^(e)—C(O)C(O)N(R^(a))—R^(e)—,—R^(e)—N(R^(a))—C(O)C(O)—R^(e)—, —R^(e)—O—R^(e)—, —R^(e)—S(O)₂—R^(e)—,—R^(e)—S(O)—R^(e)—, —R^(e)—S—R^(e)—, —R^(e)—N(R^(a))—R^(e)—,—R^(e)—N(R^(a))C(O)—R^(e)—, —R^(e)—C(O)N(R^(a))R^(e)—,—R^(e)—OC(O)N(R^(a))—R^(e)—, —R^(e)—N(R^(a))C(O)OR^(e)—,—R^(e)—N(R^(a))C(O)N(R^(b))—R^(e)—, —R^(e)—N(R^(a))S(O)₂—R^(e)—, or—R^(e)—S(O)₂N(R^(a))—R^(e)—; or

M is

where in all cases, M is linked to either a carbon or a nitrogen atom inL;

Q is hydrogen, deuterium, —N(R^(a))(R^(b)), halogen, —OR^(a), —SR^(a),—S(O)R^(a), —S(O)₂R^(a), —NO₂, —C(O)OR^(a), —CN, —C(O)N(R^(a))(R^(b)),—N(R^(a))C(O)R^(b), —N(R^(a))C(O)OR^(b), —N(R^(a))C(O)N(R^(b))₂,—C(O—R^(a))(R^(b))₂, —C(O)R^(a), —CF₃, —OCF₃, —N(R^(a))S(O)₂R^(b),—S(O)₂N(R^(a))(R^(b)), —S(O)₂N(R^(a))C(O)R^(b), an optionallysubstituted (C₁-C₆)alkyl, an optionally substituted (C₂-C₆)alkenyl, anoptionally substituted (C₂-C₆)alkynyl, an optionally substituted(C₃-C₁₀)cycloalkyl, an optionally substituted (C₁-C₁₀)heteroaryl, anoptionally substituted (C₁-C₁₀) heterocyclyl, an optionally substituted(C₆-C₁₀)aryl;

-   -   wherein in a moiety containing —N(R^(a))(R^(b)), the nitrogen,        R^(a) and R^(b) may form a ring such that —N(R^(a))(R^(b))        represents an optionally substituted (C₂-C₁₀)heterocyclyl or an        optionally substituted (C₁-C₁₀) heteroaryl linked through a        nitrogen;

R^(a) and R^(b) are each independently hydrogen, deuterium, CN, anoptionally substituted (C₁-C₁₀)alkyl, an optionally substituted(C₂-C₁₀)alkenyl, an optionally substituted (C₂-C₁₀)alkynyl, anoptionally substituted (C₁-C₁₀)alkyl-O—(C₁-C₁₀)alkyl, an optionallysubstituted (C₃-C₁₀)cycloalkyl, an optionally substituted (C₆-C₁₀)aryl,an optionally substituted (C₁-C₁₀)heteroaryl, an optionally substituted(C₁-C₁₀)heterocyclyl, an optionally substituted—(C₁-C₆)alkylene-(C₃-C₁₀)cycloalkyl, an optionally substituted—(C₁-C₆)alkylene-(C₆-C₁₀)aryl, an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heteroaryl, or an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heterocyclyl; and

R^(e) for each occurrence is independently a bond, an optionallysubstituted (C₁-C₁₀)alkylene, an optionally substituted(C₂-C₁₀)alkenylene, an optionally substituted (C₂-C₁₀)alkynylene, anoptionally substituted —(C₁-C₁₀)alkylene-O—(C₁-C₁₀)alkylene group, anoptionally substituted (C₃-C₁₀)cycloalkylene, an optionally substituted(C₆-C₁₀)arylene, an optionally substituted (C₁-C₁₀)heteroarylene, or anoptionally substituted (C₁-C₁₀)heterocyclylene;

provided that when T is N, U is CR⁴, X is NR³ and Y is C, R⁴ is not OH;

provided that when T is N, U is CR⁴, X is NR³ and Y is C, R¹ is H;

provided that when the compound is

R³ is defined as above and R⁶ is not linked to the pyrazole ring by anitrogen or oxygen atom; and

provided that when the compound is

when R³ is H, CH₃ or C(O)OH then R⁴ is not H, —C(O)OCH₂CH₃,—C(O)NH-optionally substituted phenyl, —NHC(O)-optionally substitutedphenyl or S(O)₂-phenyl.

In a second embodiment the invention provides a compound according tothe first embodiment wherein R³ is -A-D-E-G and A is a bond, optionallysubstituted (C₁-C₆)alkylene, optionally substituted(C₃-C₁₂)cycloalkylene or optionally substituted (C₂-C₆)heterocyclylene.

In a third embodiment the invention provides a compound according to theany of the foregoing embodiments wherein R³ is -A-D-E-G and D is anoptionally substituted (C₁-C₈)alkylene, optionally substituted(C₃-C₁₀)cycloalkylene, optionally substituted bridged(C₅-C₁₀)cycloalkenylene, optionally substituted (C₃-C₁₀)bridgedheterocyclylene or optionally substituted (C₂-C₁₀)heterocyclylene.

In a fourth embodiment the invention provides a compound according tothe any of the foregoing embodiments 3 wherein D is optionallysubstituted (C₁-C₆)alkylene, optionally substituted(C₃-C₆)cycloalkylene, optionally substituted bicyclo[2.2.2]octany-1-yl,optionally substituted 2,5-diazabicyclo[2.2.1]heptane, optionallysubstituted 2,6-diazabicyclo[3.2.1]octane, optionally substitutedoctahydropyrrolo[3,4-c]pyrrole, optionally substitutedoctahydropyrrolo[3,2-b]pyridine, optionally substituted 1,4-diazepane,optionally substituted cubane, optionally substituted1,4-dioxane-spiro[4.4]nonane, optionally substituted2,5-diazaspiro[3.5]nonane, optionally substituted piperidine, optionallysubstituted piperazine, optionally substituted pyrrolidine, optionallysubstituted tetrahydrofuran or optionally substituted tetrahydropyran.

In a fifth embodiment the invention provides a compound according to theany of the foregoing embodiments wherein R³ is -A-D-E-G and E is a bond,—R^(e)—, —R^(e)—C(O)—R^(e)—, —R^(e)—O—R^(e)—, —R^(e)—S(O)₂—R^(e)—,—R^(e)—N(R^(a))—R^(e)—, ═N—R^(e)—. —R^(e)—N(R^(a))C(O)—R^(e)—,—R^(e)—N(R^(a))C(O)O—R^(e)—, —R^(e)—N(R^(a))C(O)N(R^(b))—R^(e)—,—R^(e)C(O)N(R^(a))R^(e)—, —R^(e)—N(R^(a))S(O)₂—R^(e)—,—R^(e)—S(O)₂N(R^(a))—R^(e)—, —R^(e)—N(R^(a))S(O)₂N(R^(a))—R^(e)—,—R^(e)—OC(O)N(R^(a))—R^(e), —R^(e)—C(O)O—R^(e), —R^(e)—OC(O)—R^(e); or

wherein

R^(a) for each occurrence is independently hydrogen, CN, an optionallysubstituted (C₁-C₁₀)alkyl or an optionally substituted—(C₁-C₆)alkylene-(C₃-C₁₀)cycloalkyl; and

R^(e) for each occurrence is independently a bond, an optionallysubstituted (C₁-C₁₀)alkylene, an optionally substituted(C₃-C₁₀)cycloalkylene, an optionally substituted (C₆-C₁₀)arylene, anoptionally substituted (C₁-C₁₀)heteroarylene, or an optionallysubstituted (C₁-C₁₀)heterocyclylene.

In a sixth embodiment the invention provides a compound according to theany of the foregoing embodiments wherein R³ is -A-D-E-G and G ishydrogen, deuterium, —N(R^(a))(R^(b)), halogen, —OR^(a), —S(O)₂R^(a),—CN, —C(O)N(R^(a))(R^(b)), —N(R^(a))C(O)R^(b), —CF₃,—S(O)₂N(R^(a))(R^(b)), an optionally substituted —(C₁-C₆)alkyl, anoptionally substituted —(C₃-C₁₀)cycloalkyl, an optionally substituted—(C₁-C₁₀)heteroaryl, an optionally substituted —(C₁-C₁₀) heterocyclyl,or an optionally substituted —(C₆-C₁₀)aryl;

-   -   wherein in a moiety containing —N(R^(a))(R^(b)), the nitrogen,        R^(a) and R^(b) may form a ring such that —N(R^(a))(R^(b))        represents an optionally substituted (C₂-C₁₀)heterocyclyl or an        optionally substituted (C₁-C₁₀) heteroaryl linked through a        nitrogen;    -   R^(a) is independently hydrogen, CN, an optionally substituted        (C₁-C₁₀)alkyl, an optionally substituted (C₃-C₁₀)cycloalkyl, or        an optionally substituted (C₆-C₁₀)aryl.

In a seventh embodiment the invention provides a compound according tothe any of the foregoing embodiments wherein G is hydrogen, deuterium,—N(R^(a))(R^(b)), halogen, —OR^(a), —S(O)₂R^(a), —CN,—C(O)N(R^(a))(R^(b)), —N(R^(a))C(O)R^(b), —CF₃, —S(O)₂N(R^(a))(R^(b)),an optionally substituted —(C₁-C₄)alkyl, an optionally substituted—(C₃-C₆)cycloalkyl, optionally substituted azepanyl, optionallysubstituted azetidinyl, optionally substituted benzo[d]isoxazolyl,optionally substituted 4,5-dihydroisoxazolyl, optionally substitutedisothiazolidinyl, optionally substituted isothiazolyl, optionallysubstituted isoxazolyl, optionally substituted morpholinyl, optionallysubstituted oxadiazolyl, optionally substituted oxazolyl, optionallysubstituted oxetanyl, optionally substitute phenyl, optionallysubstituted piperazinyl, optionally substituted piperidinyl, optionallysubstituted pyrazinyl, optionally substituted pyrazolyl, optionallysubstituted pyridazinyl, optionally substituted pyridinyl, optionallysubstituted pyrimidinyl, optionally substituted pyrrolidinyl, optionallysubstituted pyrrolyl, optionally substituted tetrahydrofuranyl,optionally substituted tetrahydropyranyl, optionally substitutedtetrahydrothiopyranyl, optionally substituted thienyl, optionallysubstituted thiomorpholinyl, optionally substituted1,1-dioxo-thiomorpholinyl, optionally substituted thiazolyl oroptionally substituted triazolyl.

In eighth embodiment the invention provides a compound according to theany of the foregoing embodiments wherein R³ is hydrogen, optionallysubstituted (C₁-C₈)alkyl, optionally substituted (C₃-C₁₀)cycloalkyl, oroptionally substituted (C₂-C₁₀)heterocyclyl.

In a ninth embodiment the invention provides a compound according to theany of the foregoing embodiments wherein R⁶ is J-L-M-Q and J is a bond,optionally substituted (C₁-C₆)alkylene, or an optionally substituted(C₂-C₆)alkenylene.

In a tenth embodiment the invention provides a compound according to theany of the foregoing embodiments wherein R⁶ is J-L-M-Q and L is a bond,or an optionally substituted (C₁-C₈)alkylene.

In an eleventh embodiment the invention provides a compound according tothe any of the foregoing embodiments wherein R⁶ is J-L-M-Q and M is abond, —R^(e)—, —R^(e)—C(O)—R^(e)—, —R^(e)—O—R^(e)—, —R^(e)—S(O)₂—R^(e)—,—R^(e)—S(O)—R^(e)—, —R^(e)—S—R^(e)—, —R^(e)—N(R^(a))—R^(e)—,—R^(e)—N(R^(a))C(O)—R^(e)—, —R^(e)—C(O)N(R^(a))R^(e)—,—R^(e)—N(R^(a))C(O)N(R^(b))—R^(e)—, —R^(e)—N(R^(a))S(O)₂—R^(e)—, or—R^(e)—S(O)₂N(R^(a))—R^(e)—; where in all cases, M is linked to either acarbon or a nitrogen atom in L.

In a twelfth embodiment the invention provides a compound according tothe any of the foregoing embodiments wherein R⁶ is J-L-M-Q and Q ishydrogen, deuterium, —N(R^(a))(R^(b)), halogen, —OR^(a), —SR^(a),—S(O)R^(a), —S(O)₂R^(a), —NO₂, —C(O)R^(a), —CN, —C(O)N(R^(a))(R^(b)),—N(R^(a))C(O)R^(b), —N(R^(a))C(O)OR^(b), —N(R^(a))C(O)N(R^(b))₂,—C(O—R^(a))(R^(b))₂, —C(O)R^(a), —CF₃, —OCF₃, —N(R^(a))S(O)₂R^(b),—S(O)₂N(R^(a))(R^(b)), —S(O)₂N(R^(a))C(O)R^(b), an optionallysubstituted (C₁-C₆)alkyl, an optionally substituted (C₃-C₁₀)cycloalkyl,an optionally substituted (C₁-C₁₀)heteroaryl, an optionally substituted(C₁-C₁₀) heterocyclyl, an optionally substituted (C₆-C₁₀)aryl;

-   -   wherein in a moiety containing —N(R^(a))(R^(b)), the nitrogen,        R^(a) and R^(b) may form a ring such that —N(R^(a))(R^(b))        represents an optionally substituted (C₂-C₁₀)heterocyclyl or an        optionally substituted (C₁-C₁₀) heteroaryl linked through a        nitrogen;

R^(a) and R^(b) are each independently hydrogen, deuterium, anoptionally substituted (C₁-C₆)alkyl, an optionally substituted(C₂-C₁₀)alkenyl, an optionally substituted (C₃-C₆)cycloalkyl, anoptionally substituted (C₆-C₁₀)aryl, an optionally substituted(C₁-C₁₀)heteroaryl, or an optionally substituted (C₁-C₁₀)heterocyclyl.

In a thirteenth embodiment the invention provides a compound accordingto the any of the foregoing embodiments wherein T is N, U is N, X is CR³and Y is N and forms a compound of Formula (Ia)

In a fourteenth embodiment the invention provides a compound accordingto the thirteenth embodiment wherein in the compound is

-   N-(1-((6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)methyl)cyclobutyl)cyclopropanesulfonamide;-   N-(1-((6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)methyl)cyclobutyl)-2-cyanoacetamide;-   (S)-1-((1-(cyclopropylsulfonyl)pyrrolidin-3-yl)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine;-   N-((1S,3R,4R)-4-ethyl-3-fluoro-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide;-   N-((1R,3S,4S)-4-ethyl-3-fluoro-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide;-   N-((1R,3R,4S)-4-ethyl-3-fluoro-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide;-   N-((1S,3S,4R)-4-ethyl-3-fluoro-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide;-   (1S,3R)-1-[3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-isothiazolidin-2-yl-1,1-dioxide]cyclopentane;-   N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-N-methylcyclopropanesulfonamide;-   1-((1S,2R,4S)-2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine;-   (S)-5-(3-((6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)methyl)pyrrolidin-1-yl)pyrazine-2-carbonitrile;-   N-(cyclopropylmethyl)-N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide;-   N-((1S,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-2-(4-cyanophenyl)acetamide;-   N-((1S,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanecarboxamide;-   N-((1S,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-2-cyclopropylacetamide;-   N-((1S,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-4-cyanobenzamide;-   N,N-diethyl-1-(3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methanesulfonamide;-   1-((1S,2S,4R)-4-((azetidin-1-ylsulfonyl)methyl)-2-ethylcyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine;-   1-((1R,2R,4S)-4-((azetidin-1-ylsulfonyl)methyl)-2-ethylcyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine;-   1-((1R,2S,4R)-4-((azetidin-1-ylsulfonyl)methyl)-2-ethylcyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine;-   1-((1S,2R,4S)-4-((azetidin-1-ylsulfonyl)methyl)-2-ethylcyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine;-   N-((1S,3R,4S)-3-ethyl-4-(7-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropane    sulfonamide;-   N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-N-(2-hydroxyethyl)cyclopropanesulfonamide;-   5-((1R,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)pyrazine-2-carbonitrile-   N-((1R,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-4-methylaniline;-   1-((1R,3S)-3-(1H-pyrrol-1-yl)cyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine;-   1-((1S,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-1H-pyrrole-3-carbonitrile;-   N-((1R,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)aniline;-   N-((1-((6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)methyl)cyclobutyl)methyl)-2-cyanoacetamide;-   N-((1R,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-4-fluoroaniline;-   N-((1R,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-4-chloroaniline;-   N-((1R,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-3,4-dichloroaniline;-   N-((1R,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-4-methoxyaniline;-   N-((1R,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-4-methoxy-N-(4-methoxyphenyl)aniline;-   3-((3R,4R)-4-methyl-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)piperidin-1-yl)-3-oxopropanenitrile;-   1-methyl-N-((1S,3R,4S)-3-methyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-1H-pyrazole-4-sulfonamide;-   3-((1R,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)benzonitrile;-   N-((1S,3R,4S)-3-methyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)aniline;-   4-((1S,2R,4S)-4-(benzyloxy)-2-ethylcyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine;-   4-((1R,2S,4R)-4-(benzyloxy)-2-ethylcyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine;-   5-methyl-N-((1S,3R,4S)-3-methyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)isoxazole-4-sulfonamide;-   N-(4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)cyclobutanesulfonamide;-   6-((1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyloxy)nicotinonitrile;-   N-(4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)pyrrolidine-1-carboxamide;-   4-((1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyloxy)benzonitrile;-   4-((1S,3S,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyloxy)benzonitrile;-   4-methyl-N-((1S,3R,4S)-3-methyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)aniline;-   4-chloro-N-((1S,3R,4S)-3-methyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)aniline;-   3-((1S,3R,4S)-3-methyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)benzonitrile;-   4-fluoro-N-((1S,3R,4S)-3-methyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)aniline;-   N-((1S,3S,4R)-3-methyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)aniline;-   N-((1R,3R,4S)-3-methyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)aniline;-   5-((1S,3R,4S)-3-methyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)pyrazine-2-carbonitrile;-   6-((1S,3R,4S)-3-methyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)nicotinonitrile;-   6-((1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyloxy)nicotinonitrile;-   6-((1S,3S,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyloxy)nicotinonitrile;-   1-((1S,2S,4R)-2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine;-   1-((1R,2R,4S)-2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine;-   N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-3,3,3-trifluoropropane-1-sulfonamide;-   5-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)pyrazine-2-carbonitrile;-   6-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)nicotinonitrile;-   2-((1S,3R,4S)-3-methyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)thiazole-5-carbonitrile;-   N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)azetidine-1-sulfonamide;-   N-((1R,3R,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropane    sulfonamide;-   N-((1S,3S,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropane    sulfonamide;-   3-cyano-N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)azetidine-1-sulfonamide;-   N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-3,3-difluoroazetidine-1-sulfonamide;-   5-((1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyloxy)pyrazine-2-carbonitrile;-   5-((1S,3S,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyloxy)pyrazine-2-carbonitrile;-   6-((1S,3S,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyloxy)nicotinonitrile;-   6-((1R,3R,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyloxy)nicotinonitrile;-   2-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)thiazole-5-carbonitrile;-   5-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyloxy)pyrazine-2-carbonitrile;-   5-((1R,3S,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyloxy)pyrazine-2-carbonitrile;-   N-(4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)pyrrolidine-1-sulfonamide;-   5-(((1S,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methylamino)pyrazine-2-carbonitrile;-   (S)—N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-2-(trifluoromethyl)pyrrolidine-1-sulfonamide;-   N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-3,3-difluoropyrrolidine-1-sulfonamide;-   N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-4,4-difluoropiperidine-1-sulfonamide;-   N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-1-methylcyclopropane-1-sulfonamide;-   N-(4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)-1-methylcyclopropane-1-sulfonamide;-   N-(4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)azetidine-1-sulfonamide;-   6-((1S,3R,4S)-3-methyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)nicotinonitrile;-   N-((1S,3R,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopentanesulfonamide;-   5-(((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methoxy)pyrazine-2-carboxamide;-   ((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methanol;-   ((1R,3S,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methanol;-   5-(((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methoxy)pyrazine-2-carbonitrile;-   5-(((1R,3S,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methoxy)pyrazine-2-carbonitrile;-   N-(4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)-3,3-difluoroazetidine-1-sulfonamide;-   N-(3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)aniline;-   1-((1S,2R,4R)-2-ethyl-4-(5-(trifluoromethyl)pyridin-2-yloxy)cyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine;-   1-((1R,2S,4S)-2-ethyl-4-(5-(trifluoromethyl)pyridin-2-yloxy)cyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine;-   5-((1R,3S,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyloxy)pyrazine-2-carbonitrile;-   5-((1S,3R,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyloxy)pyrazine-2-carbonitrile;-   N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-2,2,2-trifluoroethanesulfonamide;-   N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-4-methylpiperazine-1-sulfonamide;-   4-((1S,3S,4R)-3-methyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyloxy)benzonitrile;-   4-((1R,3R,4S)-3-methyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyloxy)benzonitrile;-   3-(((1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyloxy)methyl)benzonitrile;-   3-(((1S,3S,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyloxy)methyl)benzonitrile;-   4-(((1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyloxy)methyl)benzonitrile;-   4-(((1S,3S,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyloxy)methyl)benzonitrile;-   1-ethyl-N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropane-1-sulfonamide;-   N-(((1R,3S,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methyl)cyclopropanesulfonamide;-   N-(((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methyl)cyclopropanesulfonamide;-   4-((1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyloxy)-2-fluorobenzonitrile;-   4-((1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyloxy)-3-fluorobenzonitrile;-   3-((1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyloxy)benzonitrile;-   N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-2-morpholinoethanesulfonamide;-   1-butyl-N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropane-1-sulfonamide;-   2-(3,3-difluoropyrrolidin-1-yl)-N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)ethanesulfonamide;-   2-(((1S,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methylamino)isonicotinonitrile;-   N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-2-methylpropane-2-sulfonamide;-   N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-2-(1H-1,2,4-triazol-1-yl)ethanesulfonamide;-   2-(4,4-difluoropiperidin-1-yl)-N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)ethanesulfonamide;-   N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-2-(2H-1,2,3-triazol-2-yl)ethanesulfonamide;-   N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-2-(1H-1,2,3-triazol-1-yl)ethanesulfonamide;-   (1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanol;-   1-((1S,2R,4R)-2-ethyl-4-(3,3,3-trifluoropropoxy)cyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine;-   N-((1S,3R,4S)-3-ethyl-4-(8-iodo-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropane    sulfonamide;-   (1S,3R,4S)—N-(2-(3,3-difluoropyrrolidin-1-ylsulfonyl)ethyl)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine;-   N-cyano-N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropane    sulfonamide;-   N-((1S,3R,4S)-3-ethyl-4-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclopentyl)cyclopropanesulfonamide;-   N-((1S,3R,4S)-3-ethyl-4-(8-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-N-(hydroxymethyl)cyclopropanesulfonamide;-   N-((1S,3S,4R)-3-(8-cyano-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-4-ethylcyclopentyl)cyclopropane    sulfonamide;-   1-((1S,2R,4S)-4-(cyclopropylmethoxy)-2-ethylcyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine;-   1-((1S,2R,4S)-4-(cyclopropylmethoxy)-2-methylcyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine;-   1-((1S,2R,4S)-2-ethyl-4-(2,2,2-trifluoro    ethylsulfonyl)cyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine;-   1-((1S,2R,4S)-2-ethyl-4-(tetrahydro-2H-pyran-4-yloxy)cyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine;-   1-((1S,2R,4S)-2-ethyl-4-((tetrahydro-2H-pyran-4-yl)methoxy)cyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine;-   1-((1R,2R,4S)-2-ethyl-4-((tetrahydro-2H-pyran-4-yl)methoxy)cyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine;-   1-((1S,2R,4R)-4-(cyclopropylmethoxy)-2-ethylcyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine;-   1-((1S,2R,4R)-2-ethyl-4-(tetrahydro-2H-pyran-4-yloxy)cyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine;-   2-(4-cyano-1H-pyrazol-1-yl)-N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)ethanesulfonamide;-   1-((1S,2R,4S)-2-ethyl-4-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)cyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine;-   1-((1R,2R,4S)-2-ethyl-4-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)cyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine;-   1-((1S,2R,4R)-2-ethyl-4-((tetrahydro-2H-pyran-4-yl)methoxy)cyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine;-   1-((1S,2R,4S)-2-ethyl-4-(2-methoxyethoxy)cyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine;-   1-((1R,2R,4S)-2-ethyl-4-(2-methoxyethoxy)cyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine;-   1-((1S,2R,4R)-2-ethyl-4-isopropoxycyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine;-   N-((3R,5R)-1-ethyl-5-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)pyrrolidin-3-yl)cyclopropanesulfonamide;-   (3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanone;-   1-((7S,8R)-8-ethyl-1,4-dioxaspiro[4.4]nonan-7-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine;-   (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-N-(2,2,2-trifluoroethyl)cyclopentanamine;-   (3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanone    O-cyclopropylmethyl oxime;-   (3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanone    O-2-(methylsulfonyl)ethyl oxime;-   (3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanone    O-cyclobutylmethyl oxime;-   1-((1S,2R,4R)-4-(4,4-dimethylcyclohexyloxy)-2-ethylcyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine;-   N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-2-methoxyethanesulfonamide;-   N-((3R,5R)-1-acetyl-5-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)pyrrolidin-3-yl)cyclopropanesulfonamide;-   1-((3S,4R)-1-(cyclopropylmethylsulfonyl)-4-ethylpyrrolidin-3-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine;-   2-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)acetic    acid;-   N-cyclopropyl-2-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)acetamide;-   3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanone    O-tetrahydro-2H-pyran-4-yl oxime;-   1-((1S,2R,4S)-4-(3,3-difluoroazetidin-1-yl)-2-ethylcyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine;-   1-((1S,2R,4S)-4-(3,3-difluoropyrrolidin-1-yl)-2-ethylcyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine;-   Dimethyl-carbamic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester;-   {3-[(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentylamino]-oxetan-3-yl}-acetonitrile;-   Cyclopropanesulfonic acid    cyanomethyl-[(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-amide;-   1-[(3R,4S)-4-Ethyl-1-(2-morpholin-4-yl-ethyl)-pyrrolidin-3-yl]-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl;-   Cyclopropanesulfonic acid    [(3R,5R)-1-(2,2-difluoro-ethyl)-5-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-pyrrolidin-3-yl]-amide;-   1-[(3R,4S)-4-Ethyl-1-(3,3,3-trifluoro-propane-1-sulfonyl)-pyrrolidin-3-yl]-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl;-   3-[(1R,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyloxy]-propionitrile;-   1-[(3R,4S)-4-Ethyl-1-(3,3,3-trifluoro-propyl)-pyrrolidin-3-yl]-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl;-   2-Cyclopropyl-1-[(3S,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-pyrrolidin-1-yl]-ethanone;-   1-[(3S,4R)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-pyrrolidin-1-yl]-2-(tetrahydro-pyran-4-yl)-ethanone;-   (3S,4R)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-pyrrolidine-1-carboxylic    acid cyclopropylmethyl-amide;-   Cyclopropanesulfonic acid    [(3R,5R)-1-ethyl-5-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-pyrrolidin-3-yl]-methyl-amide;-   (3S,4R)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-pyrrolidine-1-carboxylic    acid (tetrahydro-pyran-4-ylmethyl)-amide;-   3,3-Difluoro-cyclobutanesulfonic acid    [(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-amide;-   Cyclopropanesulfonic acid    [(1S,4S)-3,3-dimethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-amide;-   Cyclopropanesulfonic acid    [(1R,4R)-3,3-dimethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-amide;-   1-[(1S,2R,4R)-4-(4,4-Difluoro-cyclohexyloxy)-2-ethyl-cyclopentyl]-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl;-   1-[(1R,2R,4R)-4-(4,4-Difluoro-cyclohexyloxy)-2-ethyl-cyclopentyl]-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl;-   6-[(3S,4R)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-pyrrolidin-1-yl]-nicotinonitrile;-   1-[(3R,4S)-1-(3,3-Difluoro-cyclobutanesulfonyl)-4-ethyl-pyrrolidin-3-yl]-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl;-   [(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-bis-(4,4,4-trifluoro-butyl)-amine;-   1-[(1S,2R,4R)-2-Ethyl-4-(4-trifluoromethyl-cyclohexyloxy)-cyclopentyl]-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl;-   4-[(3S,4R)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-pyrrolidin-1-ylmethyl]-benzonitrile;-   3-[(3S,4R)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-pyrrolidin-1-yl]-3-oxo-propionitrile;-   1-[(1S,2R,4R)-2-Ethyl-4-(4-trifluoromethyl-cyclohexyloxy)-cyclopentyl]-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl;-   1-[(1R,2R,4R)-2-Ethyl-4-(4-trifluoromethyl-cyclohexyloxy)-cyclopentyl]-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl;-   1-[(1R,2R,4R)-2-Ethyl-4-(4-trifluoromethyl-cyclohexyloxy)-cyclopentyl]-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl;-   {3-[(3S,4R)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-pyrrolidin-1-yl]-oxetan-3-yl}-acetonitrile;-   3-[(1S,3R,4R)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyloxy]-propionitrile;-   3-[(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyloxy]-propionitrile;-   Cyclopropanesulfonic acid    (2-cyano-ethyl)-[(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-amide;-   4-[(1R,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyloxy]-cyclohexanecarbonitrile;-   4-[(1R,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyloxy]-cyclohexanecarbonitrile;-   1-((3R,4S)-1-Cyclopropanesulfonyl-4-ethyl-pyrrolidin-3-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl;-   N-[(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-N-(4,4,4-trifluoro-butyl)-acetamide;-   Cyclopropyl-carbamic acid    (1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester;-   3,3-Difluoro-azetidine-1-carboxylic acid    (1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester;-   Cyanomethyl-carbamic acid    (1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester;-   N-[(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-N-(tetrahydro-pyran-4-ylmethyl)-acetamide;-   3-[(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-1,1-dimethyl-urea;-   Dimethyl-carbamic acid    (1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester;-   (1S,3R,4S)-3-Ethyl-1-(morpholine-4-sulfonylmethyl)-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentanol;-   (1R,3R,4R)-3-Ethyl-1-(morpholine-4-sulfonylmethyl)-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentanol;-   (1S,3R,4R)-3-Ethyl-1-(morpholine-4-sulfonylmethyl)-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentanol;-   N-Cyclopropylmethyl-N-[(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-acetamide;-   1-[(1S,3R,4R)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-2-methyl-propan-2-ol;-   1-[(1R,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-2-methyl-propan-2-ol;-   1-[(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-2-methyl-propan-2-ol;-   1-[(1R,2R,4S)-4-(3-Cyclopropyl-[1,2,4]oxadiazol-5-ylmethyl)-2-ethyl-cyclopentyl]-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl;-   1-[(1S,2R,4S)-4-(3-Cyclopropyl-[1,2,4]oxadiazol-5-ylmethyl)-2-ethyl-cyclopentyl]-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl;-   1-[(1S,2R,4R)-4-(3-Cyclopropyl-[1,2,4]oxadiazol-5-ylmethyl)-2-ethyl-cyclopentyl]-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl;-   1-[(1S,2R,4R)-2-Ethyl-4-(5-methyl-isoxazol-3-ylmethoxy)-cyclopentyl]-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl;-   Oxetan-3-yl-carbamic acid    (1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester;-   Cyclobutyl-carbamic acid    (1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester;-   Cyclopropanesulfonic acid    [(1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-amide;-   {3-[(1R,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentylamino]-oxetan-3-yl}-acetonitrile;-   [(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-carbamic    acid isopropyl ester;-   [(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-oxetan-3-yl-amine;-   1-((3R,4S)-1-Benzyl-4-isopropyl-pyrrolidin-3-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl;-   3-Fluoro-propane-1-sulfonic acid    [(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-amide;-   [(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-(3-methyl-oxetan-3-yl)-amine;-   1-[(1S,2R,4R)-2-Ethyl-4-(2-morpholin-4-yl-ethoxy)-cyclopentyl]-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl;-   Carbamoylmethyl-carbamic acid    (1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester;-   4-Hydroxy-piperidine-1-carboxylic acid    (1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester;-   (2,2,2-Trifluoro-ethyl)-carbamic acid    (1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester;-   Cyclopropylmethyl-[(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-oxetan-3-yl-amine;-   Pentane-2-sulfonic acid    [(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-amide;-   3-Phenyl-propane-1-sulfonic acid    [(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-amide;-   4,4,4-Trifluoro-butane-1-sulfonic acid    [(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-amide;-   2-Ethyl-cyclopropanesulfonic acid    [(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-amide;-   2-Methyl-propane-1-sulfonic acid    [(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-amide;-   2-Phenyl-ethanesulfonic acid    [(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-amide;-   C-Cyclohexyl-N-[(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-methanesulfonamide;-   Butane-1-sulfonic acid    [(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-amide;-   Propane-2-sulfonic acid    [(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-amide;-   N-[(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-C-phenyl-methanesulfonamide;-   Propane-1-sulfonic acid    [(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-amide;-   3-Methyl-butane-1-sulfonic acid    [(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-amide;-   N-[(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-C,C-difluoro-methanesulfonamide;-   4-Cyano-butane-1-sulfonic acid    [(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-amide;-   2-Ethoxy-ethanesulfonic acid    [(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-amide;-   N-[(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-C-(tetrahydro-furan-2-yl)-methanesulfonamide;-   Tetrahydro-pyran-4-sulfonic acid    [(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-amide;-   3-Cyano-propane-1-sulfonic acid    [(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-amide;-   N-[(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-C-(5-methyl-isoxazol-3-yl)-methanesulfonamide;-   N-[(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-C-(tetrahydro-pyran-2-yl)-methanesulfonamide;-   2-Pyridin-2-yl-ethanesulfonic acid    [(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-amide;-   C-(2,2-Dichloro-cyclopropyl)-N-[1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-methanesulfonamide;-   (3S,4R)-3-Isopropyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-pyrrolidine-1-carboxylic    acid cyclobutylamide;-   (1S,3R,4S)-3-Ethyl-1-methyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentanol;-   Carbonic acid    (1S,3R,4S)-3-ethyl-4-[6-(toluene-4-sulfonyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl]-cyclopentyl    ester 4-nitro-phenyl ester;-   Cyclobutyl-carbamic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester;-   4-Hydroxy-piperidine-1-carboxylic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester;-   3-(Cyclopropylmethyl-amino)-4-[(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentylamino]-cyclobut-3-ene-1,2-dione;-   3-[(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentylamino]-4-(oxetan-3-ylamino)-cyclobut-3-ene-1,2-dione;-   3-[(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentylamino]-4-(3,3,3-trifluoro-propylamino)-cyclobut-3-ene-1,2-dione;-   [(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-methyl-oxetan-3-yl-amine;-   [(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-(3-methyl-oxetan-3-ylmethyl)-amine;-   3-Cyclopropylamino-4-[(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentylamino]-cyclobut-3-ene-1,2-dione;-   Cyanomethyl-carbamic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester;-   Cyclopropyl-carbamic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester;-   (2,2,2-Trifluoro-ethyl)-carbamic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester;-   3,3-Difluoro-azetidine-1-carboxylic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester;-   4-Cyano-piperidine-1-carboxylic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester;-   (3S,4R)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-pyrrolidine-1-carboxylic    acid (1-cyano-cyclopropyl)-amide;-   (3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-pyrrolidine-1-carboxylic    acid (1-cyano-cyclopropyl)-amide;-   (3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-pyrrolidine-1-carboxylic    acid cyclobutylamide;-   (3S,4R)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-pyrrolidine-1-carboxylic    acid cyclobutylamide;-   (3S,4R)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-pyrrolidine-1-carboxylic    acid (3-methyl-isothiazol-5-yl)-amide;-   (3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-pyrrolidine-1-carboxylic    acid (3-methyl-isothiazol-5-yl)-amide;-   (3S,4R)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-pyrrolidine-1-carboxylic    acid cyanomethyl-amide;-   (3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-pyrrolidine-1-carboxylic    acid cyanomethyl-amide;-   (2-Cyclopropyl-ethyl)-[(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-oxetan-3-yl-amine;-   Cyclopropylmethyl-[(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-(3-methyl-oxetan-3-yl)-amine;-   (3S,4R)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-pyrrolidine-1-carboxylic    acid (oxazol-4-ylmethyl)-amide;-   (3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-pyrrolidine-1-carboxylic    acid (oxazol-4-ylmethyl)-amide;-   (3S,4R)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-pyrrolidine-1-carboxylic    acid (2,2,2-trifluoro-ethyl)-amide;-   (3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-pyrrolidine-1-carboxylic    acid (2,2,2-trifluoro-ethyl)-amide;-   (2-Cyclopropyl-ethyl)-[(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-(3-methyl-oxetan-3-yl)-amine;-   3-Cyano-azetidine-1-carboxylic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester;-   Benzyl-carbamic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester;-   Oxetan-3-yl-carbamic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester;-   (1-Cyano-cyclopropyl)-carbamic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester;-   (3-Methyl-oxetan-3-yl)-carbamic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester;-   (R)-3-Hydroxy-pyrrolidine-1-carboxylic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester;-   (S)-3-Hydroxy-pyrrolidine-1-carboxylic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester;-   4-Fluoro-piperidine-1-carboxylic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester;-   (2,2-Difluoro-ethyl)-carbamic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester;-   (3,3-Difluoro-azetidin-1-yl)-[(3S,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-pyrrolidin-1-yl]-methanone;-   1-[(1S,2R,4R)-2-Ethyl-4-(pyrazol-1-yloxy)-cyclopentyl]-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl;-   (3,3-Difluoro-azetidin-1-yl)-[(3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-pyrrolidin-1-yl]-methanone;-   {2-[(3S,4R)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-pyrrolidin-1-yl]-4,5-dihydro-oxazol-4-yl}-methanol;-   (3S,4R)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-pyrrolidine-1-carboxylic    acid oxetan-3-ylamide;-   (3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-pyrrolidine-1-carboxylic    acid oxetan-3-ylamide;-   3-Fluoro-azetidine-1-carboxylic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester;-   (1-Methyl-cyclobutyl)-carbamic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester;-   (1-Hydroxy-cyclopropylmethyl)-carbamic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester;-   Methyl-oxetan-3-yl-carbamic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester;-   (3-Methyl-oxetan-3-ylmethyl)-carbamic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester;-   Phenyl-carbamic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester;-   [(3S,4R)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-pyrrolidin-1-yl]-((R)-3-hydroxy-pyrrolidin-1-yl)-methanone;-   [(3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-pyrrolidin-1-yl]-((R)-3-hydroxy-pyrrolidin-1-yl)-methanone;-   (1R,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentanecarbonitrile;-   [(3S,4R)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-pyrrolidin-1-yl]-((S)-3-hydroxy-pyrrolidin-1-yl)-methanone;-   [(3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-pyrrolidin-1-yl]-((S)-3-hydroxy-pyrrolidin-1-yl)-methanone;-   tert-Butyl-carbamic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester;-   (2,2-Dimethyl-propyl)-carbamic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester;-   (2-Methoxy-ethyl)-carbamic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester;-   (3,5-Bis-trifluoromethyl-benzyl)-carbamic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester;-   (2-Dimethylamino-ethyl)-methyl-carbamic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester; compound with trifluoro-acetic acid;-   (3-Dimethylamino-propyl)-methyl-carbamic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester; compound with trifluoro-acetic acid;-   Benzyl-isopropyl-carbamic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester;-   (R)-3-Hydroxy-piperidine-1-carboxylic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester;-   4-Methyl-piperazine-1-carboxylic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester; compound with trifluoro-acetic acid;-   4-Acetyl-piperazine-1-carboxylic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester;-   4-(2-Fluoro-phenyl)-piperazine-1-carboxylic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester; compound with trifluoro-acetic acid;-   Pyridin-2-ylmethyl-carbamic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester; compound with trifluoro-acetic acid;-   Pyridin-3-ylmethyl-carbamic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester; compound with trifluoro-acetic acid;-   Pyridin-4-ylmethyl-carbamic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester; compound with trifluoro-acetic acid;-   Isobutyl-carbamic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester;-   [(S)-1-(Tetrahydro-furan-2-yl)methyl]-carbamic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester;-   [(R)-1-(Tetrahydro-furan-2-yl)methyl]-carbamic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester;-   (2-Cyano-ethyl)-cyclopropyl-carbamic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester;-   Diisobutyl-carbamic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester;-   Azetidine-1-carboxylic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester;-   (2-Methoxy-ethyl)-methyl-carbamic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester;-   Morpholine-4-carboxylic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester;-   Thiomorpholine-4-carboxylic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester;-   (2-Dimethylamino-ethyl)-carbamic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester; compound with trifluoro-acetic acid;-   (3-Dimethylamino-propyl)-carbamic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester; compound with trifluoro-acetic acid;-   (2-Pyrrolidin-1-yl-ethyl)-carbamic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester; compound with trifluoro-acetic acid;-   (3-Pyrrolidin-1-yl-propyl)-carbamic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester; compound with trifluoro-acetic acid;-   (2-Piperidin-1-yl-ethyl)-carbamic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester; compound with trifluoro-acetic acid;-   (3-Piperidin-1-yl-propyl)-carbamic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester; compound with trifluoro-acetic acid;-   (2-Morpholin-4-yl-ethyl)-carbamic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester; compound with trifluoro-acetic acid;-   (3-Morpholin-4-yl-propyl)-carbamic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester; compound with trifluoro-acetic acid;-   1-[(1S,2R,4S)-4-(2,2-Difluoro-ethoxy)-2-ethyl-cyclopentyl]-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl;-   1-[(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyloxy]-2-methyl-propan-2-ol;-   (2-Cyclopropyl-ethyl)-[(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-(2,2,2-trifluoro-ethyl)-amine;-   Cyclopropylmethyl-[(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-(2,2,2-trifluoro-ethyl)-amine;-   Cyclopropylmethyl-[(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-(2,2,2-trifluoro-ethyl)-amine;-   1-((7S,8R)-8-Ethyl-1,4-dioxa-spiro[4.4]non-7-yl)-6-(toluene-4-sulfonyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl;-   1-[(1R,3R,4R)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-2-methyl-propan-2-ol;-   Acetic acid    (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl    ester;-   (3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-pyrrolidine-1-sulfonic    acid cyclopropylmethyl-amide;-   (3S,4R)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-pyrrolidine-1-sulfonic    acid cyclopropylmethyl-amide;-   (3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-pyrrolidine-1-carboxylic    acid (2-cyclopropyl-ethyl)-amide;-   (3S,4R)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-pyrrolidine-1-carboxylic    acid (2-cyclopropyl-ethyl)-amide;-   (3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-pyrrolidine-1-sulfonic    acid oxetan-3-ylamide;-   (3S,4R)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-pyrrolidine-1-sulfonic    acid oxetan-3-ylamide;-   [(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-oxetan-3-yl-(4,4,4-trifluoro-butyl)-amine;-   (3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentanesulfonic    acid cyclopropylamide;-   2-[(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-ethanol;-   2-[(1R,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-ethanol;-   (3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-pyrrolidine-1-sulfonic    acid cyclobutylamide;-   (3S,4R)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-pyrrolidine-1-sulfonic    acid cyclobutylamide;-   1-[(1S,2R,4S)-2-Ethyl-4-(3-methoxymethyl-[1,2,4]oxadiazol-5-ylmethyl)-cyclopentyl]-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl;-   (3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-pyrrolidine-1-sulfonic    acid amide;-   (3S,4R)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-pyrrolidine-1-sulfonic    acid amide;-   4-[(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-butyronitrile;-   4-[(1R,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-butyronitrile;-   [(1R,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-acetonitrile;-   [(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-acetonitrile;-   [(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-(5-methyl-isoxazol-3-ylmethyl)-oxetan-3-yl-amine;-   {5-[(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentylmethyl]-[1,2,4]oxadiazol-3-yl}-methanol;-   1-[(1S,2R,4S)-4-(3-Cyclopropyl-pyrazol-1-yl)-2-ethyl-cyclopentyl]-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl;-   1-[(1S,2R,4S)-4-(5-Cyclopropyl-pyrazol-1-yl)-2-ethyl-cyclopentyl]-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl;-   (3S,4R)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-pyrrolidine-1-sulfonic    acid (2,2,2-trifluoro-ethyl)-amide;-   (3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-pyrrolidine-1-sulfonic    acid (2,2,2-trifluoro-ethyl)-amide;-   1-[(1S,2R,4S)-4-(3-Cyclopropyl-[1,2,4]triazol-1-yl)-2-ethyl-cyclopentyl]-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl;-   1-[(1S,2R,4S)-4-(5-Cyclopropyl-[1,2,4]triazol-1-yl)-2-ethyl-cyclopentyl]-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl;    or-   [(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-oxetan-3-yl-(3,3,3-trifluoro-propyl)-amine.

In a fifteenth embodiment the invention provides a compound according tothe first through twelfth embodiments wherein T is CR⁶, U is N, X is CR³and Y is N and forms a compound of Formula (Ib)

In a sixteenth embodiment the invention provides a compound according tothe fifteenth embodiment wherein the compound is

-   ((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)(2,4-difluorophenyl)methanone;-   ((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)(4-(trifluoromethyl)phenyl)methanone;-   ((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)(pyridin-3-yl)methanone;-   ((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)(3-(trifluoromethyl)phenyl)methanone;-   ((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)(pyrazin-2-yl)methanone;-   ((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)(pyrimidin-5-yl)methanone;-   1-((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)-2-cyclopropylethanone;-   ((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)(phenyl)methanone;-   1-((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)-2-cyclobutylethanone;-   1-((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)-3-cyclobutylpropan-1-one;-   ((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)(1H-pyrazol-4-yl)methanone;-   ((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)(1H-pyrazol-3-yl)methanone;-   1-((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)propan-1-one;-   N-((1S,3R,4S)-3-ethyl-4-(3-(3-hydroxypropyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide;-   1-((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidine-1-carbonyl)cyclopropanecarbonitrile;-   3-((3S,4S)-4-ethyl-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-1-yl)-3-oxopropanenitrile;-   3-((3R,4R)-4-ethyl-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-1-yl)-3-oxopropanenitrile;-   N-((1S,3R,4S)-3-ethyl-4-(3-(hydroxymethyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentyl)cyclopropane    sulfonamide;-   N-((1S,3R,4S)-3-ethyl-4-(3-(2-hydroxyethyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentyl)cyclopropane    sulfonamide;-   ((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)(1-methyl-1H-pyrazol-4-yl)methanone;-   ((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)(pyridin-4-yl)methanone;-   1-((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)-2-(3-methylisoxazol-5-yl)ethanone;-   1-((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)-2-(2,4-difluorophenyl)ethanone;-   6-((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)pyridazine-3-carbonitrile;-   5-((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)pyrazine-2-carbonitrile;-   2-((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)thiazole-5-carbonitrile;-   6-((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)nicotinonitrile;-   ((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)(pyrrolidin-1-yl)methanone;-   1-((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidine-1-carbonyl)azetidine-3-carbonitrile;-   (cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-N,N,4-trimethylpiperidine-1-carboxamide;-   1-((cis)-1-(cyclopropylsulfonyl)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine;-   (cis)-N-(cyanomethyl)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidine-1-carboxamide;-   ((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)(isoxazol-5-yl)methanone;-   1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)-3,3,3-trifluoropropan-1-one;-   1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)-3-hydroxy-3-methylbutan-1-one;-   1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)-2-methoxyethanone;-   1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)-3-methoxypropan-1-one;-   1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)pent-4-yn-1-one;-   1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)-2-(4-chlorophenyl)ethanone;-   1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)-2-(3-chlorophenyl)ethanone;-   4-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidine-1-carbonyl)benzonitrile;-   1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)-3-(3-chloroisoxazol-5-yl)propan-1-one;-   3-(2-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)-2-oxoethyl)benzonitrile;-   4-(2-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)-2-oxoethyl)benzonitrile;-   1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)-2-(1H-pyrrol-2-yl)ethanone;-   1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)-2-(pyrazin-2-yl)ethanone;-   1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)-2-(tetrahydro-2H-pyran-4-yl)ethanone;-   1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)-2-(pyrimidin-2-yl)ethanone;-   5-((1S,3S,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylcyclopentylamino)pyrazine-2-carbonitrile;-   N-(4-(3-allyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)cyclopropanesulfonamide;-   N-(1-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrrolidin-3-yl)cyclopropanesulfonamide;-   N-(4-(3-propyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)cyclopropanesulfonamide;-   2-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)thiazole-5-carbonitrile;-   N-(4-(3-(2,3-dihydroxypropyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)cyclopropanesulfonamide;-   1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidine-1-carbonyl)pyrrolidine-3-carbonitrile;-   (3R,4R)—N-(4-(cyanomethyl)phenyl)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidine-1-carboxamide;-   ((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)(morpholino)methanone;-   ((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)(4-methylpiperazin-1-yl)methanone;-   ((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)(piperidin-1-yl)methanone;-   (3R,4R)—N-(2,4-difluorophenyl)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidine-1-carboxamide;-   (3R,4R)—N-(3-cyanophenyl)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidine-1-carboxamide;-   (R)-1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidine-1-carbonyl)pyrrolidine-2-carbonitrile;-   (S)-1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidine-1-carbonyl)pyrrolidine-2-carbonitrile;-   ((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)((R)-2-(trifluoromethyl)pyrrolidin-1-yl)methanone;-   ((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)((S)-2-(trifluoromethyl)pyrrolidin-1-yl)methanone;-   ((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)(3,3-difluoroazetidin-1-yl)methanone;-   2-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)benzo[d]oxazole;-   N-((1S,3R,4S)-3-ethyl-4-(3-(2-(methylsulfonyl)ethyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide;-   ((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)(azetidin-1-yl)methanone;-   (3R,4R)—N-(4-cyanophenyl)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidine-1-carboxamide;-   ((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)((R)-3-fluoropyrrolidin-1-yl)methanone;-   ((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)(3,3-difluoropyrrolidin-1-yl)methanone;-   1-((3R,4R)-4-methyl-1-(pyrrolidin-1-ylsulfonyl)piperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine;-   (R)—N-(1-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrrolidin-3-yl)cyclopropanesulfonamide;-   (S)—N-(1-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrrolidin-3-yl)cyclopropanesulfonamide;-   3-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-(trifluoromethyl)piperidin-1-yl)-3-oxopropanenitrile;-   3-((3S,4S)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-(trifluoromethyl)piperidin-1-yl)-3-oxopropanenitrile;-   N-(3-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)-3-oxopropyl)acetamide;-   ((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)(tetrahydrofuran-2-yl)methanone;-   ((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)(tetrahydrofuran-3-yl)methanone;-   ((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)(3-methoxycyclohexyl)methanone;-   1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)-3-hydroxypropan-1-one;-   1-((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine;-   1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)-4,4,4-trifluorobutan-1-one;-   ((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone;-   ((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)(tetrahydro-2H-pyran-3-yl)methanone;-   4-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)-4-oxobutanenitrile;-   ((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)(tetrahydro-2H-pyran-2-yl)methanone;-   ((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)((R)-2-(hydroxymethyl)pyrrolidin-1-yl)methanone;-   ((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)(3-methylpyrrolidin-1-yl)methanone;-   ((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)(3-fluoroazetidin-1-yl)methanone;-   ((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)((S)-3-fluoropyrrolidin-1-yl)methanone;-   ((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)((R)-2-methylpyrrolidin-1-yl)methanone;-   ((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)((R)-morpholin-3-yl)methanone;-   1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)-3-(methylsulfonyl)propan-1-one;-   ((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)(1,4-dioxan-2-yl)methanone;-   ((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)(tetrahydrothiophen-3-yl-1,1-dioxide)methanone;-   ((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)(3,3-difluorocyclobutyl)methanone;-   N-((1S,3R,4S)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylcyclopentyl)aniline;-   N-((1R,3S,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylcyclopentyl)aniline;-   3-bromo-1-cyclohexyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine;-   (R)-(3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-1-yl)(3,3-difluoroazetidin-1-yl)methanone;-   (R)-(3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-1-yl)(3,3-difluoropyrrolidin-1-yl)methanone;-   (R)-(3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-1-yl)(4,4-difluoropiperidin-1-yl)methanone;-   (R)-1-(3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carbonyl)azetidine-3-carbonitrile;-   (3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methyl-N-(pyrimidin-2-yl)piperidine-1-carboxamide;-   (3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methyl-N-(pyridin-2-yl)piperidine-1-carboxamide;-   (3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methyl-N-(pyrimidin-4-yl)piperidine-1-carboxamide;-   (3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methyl-N-(pyrazin-2-yl)piperidine-1-carboxamide;-   1-cyclohexyl-3-phenyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine;-   N-((3S,5R)-1-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-5-methylpyrrolidin-3-yl)cyclopropanesulfonamide;-   ((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)(1-methylpyrrolidin-3-yl)methanone;-   ((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)(1-methylpiperidin-4-yl)methanone;-   (3R,4R)-phenyl    3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidine-1-carboxylate;-   ((R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-1-yl)((R)-2-(trifluoromethyl)pyrrolidin-1-yl)methanone;-   (R)-1-(1-(pyrrolidin-1-ylsulfonyl)piperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine;-   (R)-(3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-1-yl)(pyrrolidin-1-yl)methanone;-   3-(1-cyclohexyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)propanoic    acid;-   (S)-1-((R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carbonyl)pyrrolidine-3-carbonitrile;-   (R)-cyclopentyl    3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate;-   (E)-N-(((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)(pyrrolidin-1-yl)methylene)cyanamide;-   4-((1R,3R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentylamino)benzonitrile;-   (R)-(3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-1-yl)(3,3-difluorocyclobutyl)methanone;-   5-((1S,3R,4S)-3-ethyl-4-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentylamino)pyrazine-2-carbonitrile;-   N-((1S,3S,4R)-3-(3-bromo-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-ethylcyclopentyl)cyclopropanesulfonamide;-   ((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)(4,4-difluorocyclohexyl)methanone;-   (R)-(3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrrolidin-1-yl)(3,3-dimethylpyrrolidin-1-yl)methanone;-   (R)-(3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-1-yl)(3,3-difluoropiperidin-1-yl)methanone;-   (R)-1-(3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carbonyl)piperidine-4-carbonitrile;-   (R)-(3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-1-yl)(thiomorpholino-1,1-dioxide)methanone;-   ((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)(azepan-1-yl)methanone;-   (R)-(3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-1-yl)(4,4-dimethylpiperidin-1-yl)methanone;-   (R)-(3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-1-yl)(4-chloropiperidin-1-yl)methanone;-   5-(((1S,3R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentyl)methylamino)pyrazine-2-carbonitrile;-   5-(((1S,3S)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentyl)methylamino)pyrazine-2-carbonitrile;-   1-((R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carbonyl)piperidine-3-carbonitrile;-   N-((3S,5R)-5-ethyl-1-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrrolidin-3-yl)cyclopropanesulfonamide;-   1-((3,3-difluoro    cyclobutyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine;-   N-(1-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrrolidin-3-yl)cyclopropanesulfonamide;-   (E)-3-(1-cyclohexyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)acrylic    acid;-   N-((1S,3S,4R)-3-(3-chloro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-ethylcyclopentyl)cyclopropane    sulfonamide;-   4-(((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclobutoxy)methyl)benzonitrile;-   5-((3S,5R)-5-ethyl-1-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrrolidin-3-ylamino)pyrazine-2-carbonitrile;-   N-((3S,5R)-5-ethyl-1-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrrolidin-3-yl)-3,3,3-trifluoropropane-1-sulfonamide;-   4-((1R,3R,4S)-3-ethyl-4-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentyloxy)benzonitrile;-   N-((1S,3S,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylcyclopentyl)-1-methylcyclopropane-1-sulfonamide;-   1-((1S,4S)-5-(3,3,3-trifluoropropylsulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine;-   N-((1S,3S,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylcyclopentyl)-3,3-difluoroazetidine-1-sulfonamide;-   N-((1S,3S,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylcyclopentyl)-3,3,3-trifluoropropane-1-sulfonamide;-   N-((1S,3S,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylcyclopentyl)-3,3-difluoropyrrolidine-1-sulfonamide;-   (S)—N-((1S,3S,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylcyclopentyl)-2-(trifluoromethyl)pyrrolidine-1-sulfonamide;-   N-(((1S,3S)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentyl)methyl)cyclopropanesulfonamide;-   N-(((1S,3R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentyl)methyl)-3,3,3-trifluoropropane-1-sulfonamide;-   N-(((1S,3S)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentyl)methyl)-3,3,3-trifluoropropane-1-sulfonamide;-   N-((1S,3S,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylcyclopentyl)-1-ethylcyclopropane-1-sulfonamide;-   1-((3aR,6aS)-5-(3,3,3-trifluoropropylsulfonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine;-   1-(6-fluoro-4-(3,3,3-trifluoropropylsulfonyl)-1,4-diazepan-1-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine;-   4-([4-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cubanyl]methoxy)benzonitrile;-   N-((3R,4S)-4-methyl-1-(3,3,3-trifluoropropylsulfonyl)piperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-amine;-   1-(2-(3,3,3-trifluoropropylsulfonyl)-2,5-diazaspiro[3.5]nonan-5-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine;-   1-((3aS,7aR)-4-(3,3,3-trifluoropropylsulfonyl)octahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine;-   1-(7-methyl-4-(3,3,3-trifluoropropylsulfonyl)-1,4-diazepan-1-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine;-   1-(5-(3,3,3-trifluoropropylsulfonyl)-2,5-diazaspiro[3.5]nonan-2-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine;-   N-(1-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-3-yl)-3,3,3-trifluoropropane-1-sulfonamide;-   1-((1R,5S)-2-(3,3,3-trifluoropropylsulfonyl)-2,6-diazabicyclo[3.2.1]octan-6-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine;-   1-cyclohexyl-3-(4-(methylsulfonyl)phenyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine;-   N-(4-(1-cyclohexyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)phenyl)methanesulfonamide;-   N-((1S,3S,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylcyclopentyl)-3-chlorobenzenesulfonamide;-   Cyclopropanesulfonic acid    [(1S,3R,4R)-3-ethyl-4-(3-trifluoromethyl-6H-2,5,6,8b-tetraaza-as-indacen-1-yl)-cyclopentyl]-amide;-   Cyclopropanesulfonic acid    [(1S,3R,4S)-3-ethyl-4-(3-trifluoromethyl-6H-2,5,6,8b-tetraaza-as-indacen-1-yl)-cyclopentyl]-amide;-   1-((1S,2R,4S)-4-Cyclopropanesulfonylamino-2-ethyl-cyclopentyl)-6H-2,5,6,8b-tetraaza-as-indacene-3-carboxylic    acid;-   1-((1R,2R,4S)-4-Cyclopropanesulfonylamino-2-ethyl-cyclopentyl)-6H-2,5,6,8b-tetraaza-as-indacene-3-carboxylic    acid;-   Cyclopropanesulfonic acid    [(1S,3R,4S)-3-methyl-4-(3-trifluoromethyl-6H-2,5,6,8b-tetraaza-as-indacen-1-yl)-cyclopentyl]-amide;-   1-[(1R,3R,4S)-3-Ethyl-4-(3-trifluoromethyl-6H-2,5,6,8b-tetraaza-as-indacen-1-yl)-cyclopentyl]-2-methyl-propan-2-ol;-   Cyclopropanesulfonic acid    {(1S,3R,4S)-3-ethyl-4-[3-(2,2,2-trifluoro-ethyl)-6H-2,5,6,8b-tetraaza-as-indacen-1-yl]-cyclopentyl}-amide;-   [(1R,3R,4S)-3-Ethyl-4-(3-trifluoromethyl-6H-2,5,6,8b-tetraaza-as-indacen-1-yl)-cyclopentyl]-acetic    acid ethyl ester or-   1-[(1S,2R,4R)-2-Ethyl-4-(3-methoxymethyl-[1,2,4]oxadiazol-5-ylmethyl)-cyclopentyl]-3-trifluoromethyl-6H-2,5,6,8b-tetraaza-as-indacene.

In a seventeenth embodiment the invention provides a compound accordingto the first through twelfth embodiments wherein T is N, U is CR⁴, X isCR³ and Y is N and forms a compound of Formula (Ic)

In an eighteenth embodiment the invention provides a compound accordingto the seventeenth embodiment wherein the compound is

-   3-((3S,4S)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylpiperidin-1-yl)-3-oxopropanenitrile;-   5-(3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidin-1-yl)pyrazine-2-carbonitrile;-   (S)-1-(3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidine-1-carbonyl)cyclopropanecarbonitrile;-   N-((1S,3R,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentyl)cyclopropanesulfonamide;-   N-((1R,3S,4S)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentyl)cyclopropane    sulfonamide;-   (S)-6-(3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidin-1-yl)nicotinonitrile;-   (R)-6-(3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidin-1-yl)nicotinonitrile;-   (S)-2-(3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidin-1-yl)thiazole-5-carbonitrile;-   (R)-2-(3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidin-1-yl)thiazole-5-carbonitrile;-   (R)-(3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidin-1-yl)(3,3-difluoroazetidin-1-yl)methanone;-   (S)-(3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidin-1-yl)(3,3-difluoroazetidin-1-yl)methanone;-   5-((1R,3S,4S)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentylamino)pyrazine-2-carbonitrile;-   5-((1S,3R,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentylamino)pyrazine-2-carbonitrile;-   5-((1R,3R,4S)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentylamino)pyrazine-2-carbonitrile;-   5-((1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentylamino)pyrazine-2-carbonitrile;-   N-(4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)bicyclo[2.2.2]octan-1-yl)cyclopropanesulfonamide;-   (R)-(3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidin-1-yl)(3,3-difluorocyclobutyl)methanone;-   (R)-(3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidin-1-yl)(3,3-difluoropyrrolidin-1-yl)methanone;-   (R)-(3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidin-1-yl)(4,4-difluoropiperidin-1-yl)methanone;-   N-((1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentyl)-3,3,3-trifluoropropane-1-sulfonamide;-   N-((1R,3R,4S)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentyl)-3,3,3-trifluoropropane-1-sulfonamide;-   N-((1R,3S,4S)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentyl)-3,3,3-trifluoropropane-1-sulfonamide;-   N-((1S,3R,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentyl)-3,3,3-trifluoropropane-1-sulfonamide;-   ((R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidin-1-yl)((R)-2-(trifluoromethyl)pyrrolidin-1-yl)methanone;-   N-((3S,5R)-5-ethyl-1-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)pyrrolidin-3-yl)cyclopropanesulfonamide;-   1-cyclohexyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine;-   N-((3S,5R)-5-ethyl-1-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)pyrrolidin-3-yl)-3,3,3-trifluoropropane-1-sulfonamide;-   3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentanamine;-   N-((1R,3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentyl)-3,3,3-trifluoropropane-1-sulfonamide;-   N-((1S,3R,4S)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentyl)-3,3,3-trifluoropropane-1-sulfonamide;-   N-((1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentyl)cyclopropanesulfonamide;-   N-((1S,3R,4S)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentyl)cyclopropanesulfonamide;-   N-((1S,3R,4S)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentyl)-3,3-difluoroazetidine-1-sulfonamide;-   3-chloro-N-((1S,3R,4S)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentyl)-4-fluorobenzenesulfonamide;-   N-((1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentyl)-3,3-difluoroazetidine-1-sulfonamide;-   N-(((1S,3R,4S)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentyl)methyl)-3,3,3-trifluoropropane-1-sulfonamide;-   N-(((1R,3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentyl)methyl)-3,3,3-trifluoropropane-1-sulfonamide;-   N-(((1S,3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentyl)methyl)-3,3,3-trifluoropropane-1-sulfonamide;-   N-(((1R,3R,4S)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentyl)methyl)-3,3,3-trifluoropropane-1-sulfonamide;-   N-((1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentyl)morpholine-4-sulfonamide;-   3,3,3-Trifluoro-propane-1-sulfonic acid    [(2S,4S,5R)-4-methyl-5-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-tetrahydro-furan-2-ylmethyl]-amide;-   3,3,3-Trifluoro-propane-1-sulfonic acid    [(2R,4R,5S)-4-methyl-5-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-tetrahydro-furan-2-ylmethyl]-amide;-   3,3,3-Trifluoro-propane-1-sulfonic acid    methyl-[(1S,3R,4S)-3-methyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-cyclopentyl]-amide;-   Azetidine-1-sulfonic acid    [(1S,3R,4S)-3-methyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-cyclopentyl]-amide;-   {3-[(1S,3R,4S)-3-Methyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-cyclopentylamino]-oxetan-3-yl}-acetonitrile;-   3,3-Difluoro-cyclobutanesulfonic acid    [(1S,3R,4S)-3-methyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-cyclopentyl]-amide;-   8-[(1S,2R,4S)-2-Methyl-4-(tetrahydro-pyran-4-yloxy)-cyclopentyl]-3H-3,4,6,8a-tetraaza-as-indacene;-   8-[(1R,2R)-2-Methyl-4-(tetrahydro-pyran-4-yloxy)-cyclopentyl]-3H-3,4,6,8a-tetraaza-as-indacene;-   3-Fluoro-azetidine-1-sulfonic acid    [(1S,3R,4S)-3-methyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-cyclopentyl]-amide;-   3-Fluoro-propane-1-sulfonic acid    [(1S,3R,4S)-3-methyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-cyclopentyl]-amide;-   Cyclopropanesulfonic acid    [(1S,3R,4S)-3-methyl-4-(7-methyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-cyclopentyl]-amide;-   Cyclopropanesulfonic acid    [(1R,3S,4R)-3-methyl-4-(7-methyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-cyclopentyl]-amide;-   2-Cyano-N-[(1S,3R,4S)-3-methyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-cyclopentyl]-acetamide;-   8-[(1S,2R,4R)-2-Methyl-4-(tetrahydro-pyran-4-yloxy)-cyclopentyl]-3H-3,4,6,8a-tetraaza-as-indacene;-   (2-Cyclopropyl-ethyl)-[(1S,3R,4S)-3-methyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-cyclopentyl]-oxetan-3-yl-amine;-   Cyclopropylmethyl-[(1S,3R,4S)-3-methyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-cyclopentyl]-oxetan-3-yl-amine;-   (3R,4S)-3-Ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-pyrrolidine-1-carboxylic    acid (2,2,2-trifluoro-ethyl)-amide; or-   (3S,4R)-3-Ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-pyrrolidine-1-carboxylic    acid (2,2,2-trifluoro-ethyl)-amide.

In a nineteenth embodiment the invention provides a compound accordingto the first through twelfth embodiments wherein T is CR⁶, U is CR⁴, Xis CR³ and Y is N and forms a compound of Formula (Id)

In a twentieth embodiment the invention provides a compound according tothe nineteenth embodiment wherein the compound isN-(4-(3H-dipyrrolo[1,2-a:2′,3′-e]pyrazin-8-yl)bicyclo[2.2.2]octan-1-yl)cyclopropanesulfonamide.

In a twenty-first embodiment the invention provides a compound accordingto the first through twelfth embodiments wherein T is CR⁶, U is N, X isNR³ and Y is C and forms a compound of Formula (Ie)

In a twenty-second embodiment the invention provides a compoundaccording to the twenty-first embodiment wherein the compound is

-   (R)-1-(3-(pyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidine-1-carbonyl)cyclopropanecarbonitrile;    or-   (S)-1-(3-(pyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidine-1-carbonyl)cyclopropanecarbonitrile.

In a twenty-third embodiment the invention provides a compound accordingto the first through twelfth embodiments wherein T is O, U is N, X isCR³ and Y is C and forms a compound of Formula (If)

In a twenty-fourth embodiment the invention provides a compoundaccording to the first through twelfth embodiments wherein T is NR⁶, Uis N, X is CR³ and Y is C and forms a compound of Formula (Ig)

In a twenty-fifth embodiment the invention provides a compound accordingto the twenty-fourth embodiment wherein the compound is

-   1-((1R,2R,4S)-2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine;-   1-((1S,2S,4R)-2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine;    or-   N-(4-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)bicyclo[2.2.2]octan-1-yl)cyclopropanesulfonamide.

In a twenty-sixth embodiment the invention provides a compound accordingto the first through twelfth embodiments wherein T is CR⁶, U is CR⁴, Xis NR³ and Y is C and forms a compound of Formula (Ih)

In a twenty-seventh embodiment the invention provides a compoundaccording to the twenty-sixth embodiment wherein the compound is

-   1-cyclohexyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine;-   1-cyclohexyl-2-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine;    or-   1-cyclohexyl-2-(trifluoromethyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine.

In a twenty-eighth embodiment the invention provides a compoundaccording to the first through twelfth embodiments wherein T is S, U isN, X is CR³ and Y is C and forms a compound of Formula (Ii)

In a twenty-ninth embodiment the invention provides a compound accordingto the first through twelfth embodiments wherein T is N, U is CR⁴, X isNR³ and Y is C and forms a compound of formula (Ij)

In a thirtieth embodiment the invention provides a compound according tothe twenty-ninth embodiment wherein the compound is

-   N-((1S,3R,4S)-3-ethyl-4-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclopentyl)cyclopropanesulfonamide;-   N-((1S,3S,4R)-3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-4-methylcyclopentyl)cyclopropanesulfonamide;-   N-((1S,3S,4R)-3-(2-cyclopropylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-4-methylcyclopentyl)cyclopropanesulfonamide;-   N-((1S,3R,4S)-3-methyl-4-(2-methylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclopentyl)cyclopropanesulfonamide;-   Cyclopropanesulfonic acid    [(1S,3R,4S)-3-methyl-4-(2-trifluoromethyl-imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-cyclopentyl]-amide;-   Cyclopropanesulfonic acid    [(1S,3R,4S)-3-ethyl-4-(2-trifluoromethyl-imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-cyclopentyl]-amide;-   Cyclopropanesulfonic acid    [(1S,3S,4R)-3-(2-difluoromethyl-imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-4-ethyl-cyclopentyl]-amide;-   Cyclopropanesulfonic acid    [(1S,3R,4S)-3-ethyl-4-(2-methyl-imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-cyclopentyl]-amide;-   Cyclopropanesulfonic acid    [(1S,3S,4R)-3-(2-amino-imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-4-ethyl-cyclopentyl]-amide.

according to the first through twelfth embodiments wherein is N, U is N,X is NR³ and Y is C and forms a compound of Formula (Ik)

In a thirty-second embodiment the invention provides a compoundaccording to the thirty-first embodiment wherein the compound is

-   Cyclopropanesulfonic acid    [(1S,3R,4S)-3-ethyl-4-(6H)-[1,2,3]triazolo[4,5-d]pyrrolo[2,3-b]pyridin-1-yl)-cyclopentyl]-amide.

In a thirty-third embodiment the invention provides a compound ofFormula (II) wherein the compound is

pharmaceutically acceptable salts, pro-drugs, biologically activemetabolites, stereoisomers and isomers thereof wherein

R¹, and R² are independently hydrogen, deuterium, —N(R^(a))(R^(b)),halogen, —OR^(a), —SR^(a), —S(O)R^(a), —S(O)₂R^(a), —NO₂, —C(O)OR^(a),—CN, —C(O)N(R^(a))(R^(b)), —N(R^(a))C(O)(R^(b)), —C(O)R^(a),—C(OH)R^(a)R^(b), —N(R^(a))S(O)₂—R^(b), —S(O)₂N(R^(a))(R^(b)), —CF₃,—OCF₃, optionally substituted (C₁-C₆)alkyl, optionally substituted(C₂-C₆)alkenyl, optionally substituted (C₂-C₆)alkynyl, optionallysubstituted (C₃-C₁₀)cycloalkyl, optionally substituted(C₁-C₁₀)heteroaryl, optionally substituted (C₁-C₁₀) heterocyclyl, oroptionally substituted (C₆-C₁₀)aryl;

-   -   wherein in a moiety containing —N(R^(a))(R^(b)), the nitrogen,        R^(a) and R^(b) may form a ring such that —N(R^(a))(R^(b))        represents an optionally substituted (C₂-C₁₀)heterocyclyl or        optionally substituted (C₁-C₁₀)heteroaryl linked through a        nitrogen;

R³ is hydrogen, an optionally substituted bridged (C₅-C₁₂)cycloalkyl,optionally substituted bridged (C₂-C₁₀)heterocyclyl, optionallysubstituted (C₁-C₈)alkyl, optionally substituted (C₃-C₁₀)cycloalkyl,optionally substituted (C₃-C₈)cycloalkenyl, optionally substituted(C₆-C₁₀)aryl, optionally substituted (C₁-C₁₀)heteroaryl, optionallysubstituted (C₂-C₁₀)heterocyclyl; or

R³ is -A-D-E-G, wherein:

A is a bond, —C(O)—, optionally substituted (C₁-C₆)alkylene, optionallysubstituted (C₂-C₆)alkenylene, optionally substituted (C₂-C₆)alkynylene,optionally substituted (C₃-C₁₂)cycloalkylene, optionally substituted(C₂-C₆)heterocyclylene, —C(O)N(R^(a))—R^(e)—, —N(R^(a))C(O)—R^(e)—,—O—R^(e)—, —N(R^(a))—R^(e)—, —S—R^(e)—, —S(O)₂—R^(e)—, —S(O)R^(e)—,—C(O—R^(a))(R^(b))—R^(e)—, —S(O)₂N(R^(a))—R^(e)—, —N(R^(a))S(O)₂—R^(e)—or —N(R^(a))C(O)N(R^(b))—R^(e)—;

D is an optionally substituted (C₁-C₈)alkylene, optionally substitutedbridged (C₅-C₁₂)cycloalkylene, optionally substituted(C₃-C₁₀)cycloalkylene, optionally substituted bridged(C₅-C₁₀)cycloalkenylene, optionally substituted (C₃-C₁₀)cycloalkenylene,optionally substituted (C₆-C₁₀)arylene, optionally substituted(C₁-C₁₀)heteroarylene, optionally substituted bridged(C₂-C₁₀)heterocyclylene or an optionally substituted(C₂-C₁₀)heterocyclylene;

E is a bond, —R^(e)—, —R^(e)—C(═NCN)—R^(e)—, —R^(e)—C(O)—R^(e)—,—R^(e)—C(O)C(O)—R^(e)—, —R^(e)—C(O)O—R^(e)—,—R^(e)—C(O)C(O)N(R^(a))—R^(e)—, —R^(e)—N(R^(a))—C(O)C(O)—R^(e)—,—R^(e)—O—R^(e)—, —R^(e)—S(O)₂—R^(e)—, —R^(e)—S(O)—R^(e)—,—R^(e)—S—R^(e)—, —R^(e)—N(R^(a))—R^(e)—, ═N—R^(e)—,—R^(e)—N(R^(a))C(O)—R^(e)—, —R^(e)C(O)N(R^(a))R^(e)—,—R^(e)—OC(O)N(R^(a))—R^(e)—, —R^(e)—N(R^(a))C(O)OR^(e)—,—R^(e)—OC(O)—R^(e), —R^(e)—OC(O)—O—R^(e),—R^(e)—N(R^(a))C(O)N(R^(b))—R^(e)—, —R^(e)—N(R^(a))S(O)₂—R^(e)—,—R^(e)—S(O)₂N(R^(a))—R^(e)—, or —R^(e)—N(R^(a))S(O)₂N(R^(a))—R^(e)—; or

E is

where in all cases, E is linked to either a carbon or a nitrogen atom inD;

G is hydrogen, deuterium, —N(R^(a))(R^(b)), halogen, —OR^(a), —SR^(a),—S(O)R^(a), —S(O)₂R^(a), —NO₂, —C(O)OR^(a), —CN, —C(O)N(R^(a))(R^(b)),—N(R^(a))C(O)R^(b), —N(R^(a))C(O)OR^(b), —OC(O)N(R^(a)),—N(R^(a))C(O)N(R^(b))₂, —C(O—R^(a))(R^(b))₂, —C(O)R^(a), —CF₃, —OCF₃,—N(R^(a))S(O)₂R^(b), —S(O)₂N(R^(a))(R^(b)), —S(O)₂N(R^(a))C(O)R^(b), anoptionally substituted —(C₁-C₆)alkyl, an optionally substituted—(C₂-C₆)alkenyl, an optionally substituted —(C₂-C₆)alkynyl, anoptionally substituted —(C₃-C₁₀)cycloalkyl, an optionally substituted—(C₁-C₁₀)heteroaryl, an optionally substituted —(C₁-C₁₀) heterocyclyl,an optionally substituted —(C₆-C₁₀)aryl;

-   -   wherein in a moiety containing —N(R^(a))(R^(b)), the nitrogen,        R^(a) and R^(b) may form a ring such that —N(R^(a))(R^(b))        represents an optionally substituted (C₂-C₁₀)heterocyclyl or an        optionally substituted (C₁-C₁₀) heteroaryl linked through a        nitrogen;

R^(a) and R^(b) are each independently hydrogen, deuterium, CN, anoptionally substituted (C₁-C₁₀)alkyl, an optionally substituted(C₂-C₁₀)alkenyl, an optionally substituted (C₂-C₁₀)alkynyl, anoptionally substituted (C₁-C₁₀)alkyl-O—(C₁-C₁₀)alkyl, an optionallysubstituted (C₃-C₁₀)cycloalkyl, an optionally substituted (C₆-C₁₀)aryl,an optionally substituted (C₁-C₁₀)heteroaryl, an optionally substituted(C₁-C₁₀)heterocyclyl, an optionally substituted—(C₁-C₆)alkylene-(C₃-C₁₀)cycloalkyl, an optionally substituted—(C₁-C₆)alkylene-(C₆-C₁₀)aryl, an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heteroaryl, or an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heterocyclyl; and

R^(e) for each occurrence is independently a bond, an optionallysubstituted (C₁-C₁₀)alkylene, an optionally substituted(C₂-C₁₀)alkenylene, an optionally substituted (C₂-C₁₀)alkynylene, anoptionally substituted —(C₁-C₁₀)alkylene-O—(C₁-C₁₀)alkylene group, anoptionally substituted (C₃-C₁₀)cycloalkylene, an optionally substituted(C₆-C₁₀)arylene, an optionally substituted (C₁-C₁₀)heteroarylene, or anoptionally substituted (C₁-C₁₀)heterocyclylene.

In a thirty-fourth embodiment the invention provides a compoundaccording to the thirty-third embodiment wherein the compound is

-   1-Cyclohexyl-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h][1,6]naphthyridine;-   Cyclopropanesulfonic acid    [(1S,3R,4S)-3-ethyl-4-(3,6,7,8-tetrahydro-3,4,9-triaza-cyclopenta[a]naphthalen-9-yl)-cyclopentyl]-amide;    or-   Cyclopropanesulfonic acid    [(1S,3S,4R)-3-(3,6-dihydro-2H-dipyrrolo[2,3-b;2′,3′-d]pyridin-1-yl)-4-ethyl-cyclopentyl]-amide.

In a thirty-fifth embodiment the invention provides a pharmaceuticalcomposition comprising a compound of Formula (I) or Formula (II) asdefined in any of the foregoing embodiments

a pharmaceutically acceptable carrier and excipient and a secondtherapeutic agent selected from the group consisting of cytokinesuppressive anti-inflammatory drugs, antibodies to or antagonists ofother human cytokines or growth factors, IL-1, IL-2, IL-3, IL-4, IL-5,IL-6, IL-7, IL-8, IL-12, IL-15, IL-16, IL-21, IL-23, interferons,EMAP-II, GM-CSF, FGF, PDGF, CTLA or their ligands including CD154,HUMIRA™, REMICADE™, SIMPONI™ (golimumab), CIMZIA™, ACTEMRA™, CDP 571,soluble p55 or p75 TNF receptors, ENBREL™, Lenercept, TNFα convertingenzyme inhibitors, IL-1 inhibitors, Interleukin 11, IL-18 antagonists,IL-12 antagonists, IL-12 antibodies, soluble IL-12 receptors, IL-12binding proteins, non-depleting anti-CD4 inhibitors FK506, rapamycin,mycophenolate mofetil, leflunomide, NSAIDs, ibuprofen, corticosteroids,phosphodiesterase inhibitors, adensosine agonists, antithromboticagents, complement inhibitors, adrenergic agents, IL-1β convertingenzyme inhibitors, T-cell signalling kinase inhibitors,metalloproteinase inhibitors, sulfasalazine, 6-mercaptopurines,derivatives p75TNFRIgG, sIL-1RI, sIL-1RII, sIL-6R, celecoxib,hydroxychloroquine sulfate, rofecoxib, infliximab, naproxen, valdecoxib,sulfasalazine, meloxicam, acetate, gold sodium thiomalate, aspirin,triamcinolone acetonide, propoxyphene napsylate/apap, folate,nabumetone, diclofenac, piroxicam, etodolac, diclofenac sodium,oxaprozin, oxycodone HCl, hydrocodone bitartrate/apap, diclofenacsodium/misoprostol, fentanyl, anakinra, tramadol HCl, salsalate,sulindac, cyanocobalamin/fa/pyridoxine, acetaminophen, alendronatesodium, morphine sulfate, lidocaine hydrochloride, indomethacin,glucosamine sulf/chondroitin, amitriptyline HCl, sulfadiazine, oxycodoneHCl/acetaminophen, olopatadine HCl misoprostol, naproxen sodium,omeprazole, cyclophosphamide, rituximab, IL-1 TRAP, MRA, CTLA4-IG, IL-18BP, anti-IL-12, anti-IL15, VX-740, Roflumilast, IC-485, CDC-801, S1P1agonists, FTY720, PKC family inhibitors, Ruboxistaurin, AEB-071,Mesopram, methotrexate, leflunomide, corticosteroids, budenoside,dexamethasone, sulfasalazine, 5-aminosalicylic acid, olsalazine, IL-1βconverting enzyme inhibitors, IL-1ra, T cell signaling inhibitors,tyrosine kinase inhibitors, 6-mercaptopurines, IL-11, mesalamine,prednisone, azathioprine, mercaptopurine, infliximab, methylprednisolonesodium succinate, diphenoxylate/atrop sulfate, loperamide hydrochloride,omeprazole, folate, ciprofloxacin/dextrose-water, hydrocodone,bitartrate/apap, tetracycline hydrochloride, fluocinonide,metronidazole, thimerosal/boric acid, cholestyramine/sucrose,ciprofloxacin hydrochloride, hyoscyamine sulfate, meperidinehydrochloride, midazolam hydrochloride, oxycodone HCl/acetaminophen,promethazine hydrochloride, sodium phosphate,sulfamethoxazole/trimethoprim, polycarbophil, propoxyphene napsylate,hydrocortisone, multivitamins, balsalazide disodium, codeinephosphate/apap, colesevelam HCl, cyanocobalamin, folic acid,levofloxacin, natalizumab, interferon-gamma, methylprednisolone,azathioprine, cyclophosphamide, cyclosporine, methotrexate,4-aminopyridine, tizanidine, interferon-β1a, AVONEX®, interferon-β1b,BETASERON®, interferon α-n3, interferon-α, interferon β1A-IF,Peginterferon α 2b, Copolymer 1, COPAXONE®, hyperbaric oxygen,intravenous immunoglobulin, cladribine, cyclosporine, FK506,mycophenolate mofetil, leflunomide, NSAIDs, corticosteroids,prednisolone, phosphodiesterase inhibitors, adensosine agonists,antithrombotic agents, complement inhibitors, adrenergic agents,antiinflammatory cytokines, interferon-β, IFNβ1a, IFNβ1b, copaxone,corticosteroids, caspase inhibitors, inhibitors of caspase-1, antibodiesto CD40 ligand and CD80, alemtuzumab, dronabinol, daclizumab,mitoxantrone, xaliproden hydrochloride, fampridine, glatiramer acetate,natalizumab, sinnabidol, α-immunokine NNSO3, ABR-215062, AnergiX.MS,chemokine receptor antagonists, BBR-2778, calagualine, CPI-1189,liposome encapsulated mitoxantrone, THC.CBD, cannabinoid agonists,MBP-8298, mesopram, MNA-715, anti-IL-6 receptor antibody, neurovax,pirfenidone allotrap 1258 (RDP-1258), sTNF-R1, talampanel,teriflunomide, TGF-beta2, tiplimotide, VLA-4 antagonists, interferongamma antagonists, IL-4 agonists, diclofenac, misoprostol, naproxen,meloxicam, indomethacin, diclofenac, methotrexate, azathioprine,minocyclin, prednisone, etanercept, rofecoxib, sulfasalazine, naproxen,leflunomide, methylprednisolone acetate, indomethacin,hydroxychloroquine sulfate, prednisone, sulindac, betamethasone dipropaugmented, infliximab, methotrexate, folate, triamcinolone acetonide,diclofenac, dimethylsulfoxide, piroxicam, diclofenac sodium, ketoprofen,meloxicam, methylprednisolone, nabumetone, tolmetin sodium,calcipotriene, cyclosporine, diclofenac sodium/misoprostol,fluocinonide, glucosamine sulfate, gold sodium thiomalate, hydrocodonebitartrate/apap, risedronate sodium, sulfadiazine, thioguanine,valdecoxib, alefacept, and efalizumab, diclofenac, naproxen, ibuprofen,piroxicam, indomethacin, COX2 inhibitors, rofecoxib, valdecoxib,hydroxychloroquine, steroids, prednisolone, budenoside, dexamethasone,cytotoxics, azathioprine, cyclophosphamide, mycophenolate mofetil,inhibitors of PDE4, purine synthesis inhibitor, sulfasalazine,5-aminosalicylic acid, olsalazine, Imuran®, CTLA-4-IgG, anti-B7 familyantibodies, anti-PD-1 family antibodies, anti-cytokine antibodies,fonotolizumab, anti-IFNg antibody, anti-receptor receptor antibodies,anti-IL-6 receptor antibody, antibodies to B-cell surface molecules, LJP394, Rituximab, anti-CD20 antibody and lymphostat-B.

DETAILED DESCRIPTION OF THE INVENTION

Protein kinases are a broad and diverse class, of over 500 enzymes, thatinclude oncogenes, growth factors receptors, signal transductionintermediates, apoptosis related kinases and cyclin dependent kinases.They are responsible for the transfer of a phosphate group to specifictyrosine, serine or threonine amino acid residues, and are broadlyclassified as tyrosine and serine/threonine kinases as a result of theirsubstrate specificity.

The Jak family kinases (Jak1, Jak2, Jak3 and Tyk2) are cytoplasmictyrosine kinases that associate with membrane bound cytokine receptors.Cytokine binding to their receptor initiates Jak kinase activation viatrans and autophosphorylation processes. The activated Jak kinasesphosphorylate residues on the cytokine receptors creatingphosphotyrosine binding sites for SH2 domain containing proteins such asSignal Transduction Activators of Transcript (STAT) factors and othersignal regulators transduction such as suppressor of cytokine signaling(SOCS) proteins and SH2 domain-containing inositol 5′-phosphatases(SHIP). Activation of STAT factors via this process leads to theirdimerization, nuclear translocation and new mRNA transcription resultingin expression of immunocyte proliferation and survival factors as wellas additional cytokines, chemokines and molecules that facilitatecellular trafficking (see Journal of Immunology, 2007, 178, p. 2623).Jak kinases transduce signals for many different cytokine families andhence potentially play roles in diseases with widely differentpathologies including but not limited to the following examples. BothJak1 and Jak3 control signaling of the so-called common gamma chaincytokines (IL2, IL4, IL7, IL9, IL15 and IL21), hence simultaneousinhibition of either Jak1 or Jak3 could be predicted to impact Th1mediated diseases such as rheumatoid arthritis via blockade of IL2, IL7and IL15 signaling. On the other hand, IL2 signaling has recently beenshown to be essential for development and homeostasis of T-regulatorycells (Malek T R et al., Immunity, 2002, 17(2), p. 167-78). Thus, basedon genetic data, blockade of IL2 signaling alone is predicted to resultin autoimmunity (Yamanouchi J et al., Nat. Genet., 2007, 39(3), p.329-37, and Willerford D M et al., Immunity, 1995, 3(4), p. 521-30). Th2mediated diseases such as asthma or atopic dermatitis via IL4 and IL9signaling blockade. Jak1 and Tyk2 mediate signaling of IL13 (see Int.Immunity, 2000, 12, p. 1499). Hence, blockade of these may also bepredicted to have a therapeutic effect in asthma. These two kinases arealso thought to mediate Type I interferon signaling; their blockadecould therefore be predicted to reduce the severity of systemic lupuserythematosus (SLE). Tyk2 and Jak2 mediate signaling of IL12 and IL23.In fact, blockade of these cytokines using monoclonal antibodies hasbeen effective in treating psoriasis. Therefore blockade of this pathwayusing inhibitors of these kinases could be predicted to be effective inpsoriasis as well. In summary, this invention describes small-moleculecompounds that inhibit, regulate and/or modulate Jak family kinaseactivity that is pivotal to several mechanisms thought critical to theprogression of autoimmune diseases including, but not limited to,rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiplesclerosis (MS), Crohn's disease, psoriasis and asthma.

Several pathologically significant cytokines signal via Jak1 alone(Guschin D, et al., EMBO J. 1995 Apr. 3; 14(7):1421-9; Parganas E, etal., Cell. 1998 May 1; 93(3):385-95; Rodig S. J., et al., Cell. 1998 May1; 93(3):373-83). Blockade of one of these, IL6, using an IL6Rneutralizing antibody, has been shown to significantly improve diseasescores in human rheumatoid arthritis patients (Nishimoto N. et al., AnnRheum Dis., 2007, 66(9), p. 1162-7). Similarly, blockaded of GCSFsignaling, which is also mediated by Jak1 alone, using neutralizingmonoclonal antibodies or target gene deletion protects mice fromexperimental arthritis (Lawlor K. E. et al., Proc Natl Acad Sci U.S.A.,2004, 101(31), p. 11398-403). Accordingly, the identification ofsmall-molecule compounds that inhibit, regulate and/or modulate thesignal transduction of kinases, such as Jak1, is a desirable means toprevent or treat autoimmune diseases or other diseases related toabberant Jak1 function.

Jak2 is also activated in a wide variety of human cancers such asprostate, colon, ovarian and breast cancers, melanoma, leukemia andother haematopoietic malignancies. In addition, somatic point mutationof the Jak2 gene has been identified to be highly associated withclassic myeloproliferative disorders (MPD) and infrequently in othermyeloid disorders. Constitutive activation of Jak2 activity is alsocaused by chromosomal translocation in hematopoeitic malignancies. Ithas also been shown that inhibition of the Jak/STAT pathway, and inparticular inhibition of Jak2 activity, results in anti-proliferativeand pro-apoptotic effects largely due to inhibition of phosphorylationof STAT. Furthermore, pharmacological modulation or inhibition of Jak2activity could effectively block tumor growth and induce apoptosis byreducing the STAT phosphorylation in cell culture and human tumorxenografts in vivo. Accordingly, the identification of small-moleculecompounds that inhibit, regulate and/or modulate the signal transductionof kinases, particularly Jak2, is desirable as a means to treat orprevent diseases and conditions associated with cancers.

Jak kinases also transmit signals regulating essential physiologicalprocesses whose inhibition could be undesirable. For example Jak2mediates the signaling of Erythropoetin (Epo) andGranulocyte/Monocyte-Colony Stimulating Factor (GM-CSF). Individualswith genetic, congenital or acquired defects in these signaling pathwayscan develop potentially life-threatening complications such as anemiaand neutrophil dysfunction. Accordingly, one non-limiting aspect of thisinvention also relates to a method to identify compounds that may have afavorable safety profile as a result of them selectively avoidinginhibition of Jak2.

The protein kinase C family is a group of serine/threonine kinases thatcomprises twelve related isoenzymes. Its members are encoded bydifferent genes and are sub-classified according to their requirementsfor activation. The classical enzymes (cPKC) require diacylglycerol(DAG), phosphatidylserine (PS) and calcium for activation. The novelPKC's (nPKC) require DAG and PS but are calcium independent. Theatypical PKC's (aPKC) do not require calcium or DAG.

PKCtheta is a member of the nPKC sub-family (Baier, G., et al., J. Biol.Chem., 1993, 268, 4997). It has a restricted expression pattern, foundpredominantly in T cells and skeletal muscle (Mischak, H. et al., FEBSLett., 1993, 326, p. 51), with some expression reported in mast cells(Liu, Y. et al., J. Leukoc. Biol., 2001, 69, p. 831) and endothelialcells (Mattila, P. et al., Life Sci., 1994, 55, p. 1253).

Upon T cell activation, a supramolecular activation complex (SMAC) formsat the site of contact between the T cell and the antigen presentingcell (APC). PKCtheta is the only PKC isoform found to localize at theSMAC (Monks, C. et al., Nature, 1997, 385, 83), placing it in proximitywith other signaling enzymes that mediate T cell activation processes.

In another study (Baier-Bitterlich, G. et al., Mol. Cell. Biol., 1996,16, 842) the role of PKCtheta in the activation of AP-1, a transcriptionfactor important in the activation of the IL-2 gene, was confirmed. Inunstimulated T cells, constitutively active PKCtheta stimulated AP-1activity while in cells with dominant negative PKCtheta, AP-1 activitywas not induced upon activation by PMA.

Other studies showed that PKCtheta, via activation of IκB kinase beta,mediates activation of NF-κB induced by T cell receptor/CD28co-stimulation (N. Coudronniere et al., Proc. Nat. Acad. Sci. U.S.A.,2000, 97, p. 3394; and Lin, X. et al., Mol. Cell. Biol., 2000, 20, p.2933).

Proliferation of peripheral T cells from PKCtheta knockout mice, inresponse to T cell receptor (TCR)/CD28 stimulation was greatlydiminished compared to T cells from wild type mice. In addition, theamount of IL-2 released from the T cells was also greatly reduced (Sun,Z. et al., Nature, 2000, 404, p. 402). It has also been shown thatPKCtheta-deficient mice show impaired pulmonary inflammation and airwayhyperresponsiveness (AHR) in a Th2-dependent murine asthma model, withno defects in viral clearance and Th1-dependent cytotoxic T cellfunction (Berg-Brown, N. N. et al., J. Exp. Med., 2004, 199, p. 743;Marsland, B. J. et al., J. Exp. Med., 2004, 200, p. 181). The impairedTh2 cell response results in reduced levels of IL-4 and immunoglobulin E(IgE), contributing to the AHR and inflammatory pathophysiology.Otherwise, the PKCtheta knockout mice seemed normal and fertile.

Evidence also exists that PKCtheta participates in the IgE receptor(FcεRI)-mediated response of mast cells (Liu, Y. et al., J. Leukoc.Biol., 2001, 69, p. 831). In human-cultured mast cells (HCMC), it hasbeen demonstrated that PKC kinase activity rapidly localizes to themembrane following FcεRI cross-linking (Kimata, M. et al., Biochem.Biophys. Res. Commun., 1999, 257(3), p. 895). A recent study examiningin vitro activity of bone marrow mast cells (BMMC) derived fromwild-type and PKCtheta-deficient mice shows that upon FceRI crosslinking, BMMCs from PKCtheta-deficient mice reduced levels of IL-6,tumor necrosis factor-alpha (TNFα) and IL-13 in comparison with BMMCsfrom wild-type mice, suggesting a potential role for PKCtheta in mastcell cytokine production in addition to T cell activation (Ciarletta, A.B. et al., poster presentation at the 2005 American Thoracic SocietyInternational Conference).

The studies cited above and others studies confirm the critical role ofPKCtheta in T cells activation and in mast cell (MC) signaling. Thus aninhibitor of PKCtheta would be of therapeutic benefit in treatingimmunological disorders and other diseases mediated by the inappropriateactivation of T cells and MC signaling.

Many of the kinases, whether a receptor or non-receptor tyrosine kinaseor a S/T kinase have been found to be involved in cellular signalingpathways involved in numerous pathogenic conditions, includingimmunomodulation, inflammation, or proliferative disorders such ascancer.

Many autoimmune diseases and disease associated with chronicinflammation, as well as acute responses, have been linked to excessiveor unregulated production or activity of one or more cytokines.

The compounds of the invention are also useful in the treatment ofcardiovascular disorders, such as acute myocardial infarction, acutecoronary syndrome, chronic heart failure, myocardial infarction,atherosclerosis, viral myocarditis, cardiac allograft rejection, andsepsis-associated cardiac dysfunction. Furthermore, the compounds of thepresent invention are also useful for the treatment of central nervoussystem disorders such as meningococcal meningitis, Alzheimer's diseaseand Parkinson's disease.

The compounds of the invention are also useful in the treatment of anocular condition, a cancer, a solid tumor, a sarcoma, fibrosarcoma,osteoma, melanoma, retinoblastoma, a rhabdomyosarcoma, glioblastoma,neuroblastoma, teratocarcinoma, hypersensitivity reactions, hyperkineticmovement disorders, hypersensitivity pneumonitis, hypertension,hypokinetic movement disorders, aordic and peripheral aneuryisms,hypothalamic-pituitary-adrenal axis evaluation, aortic dissection,arterial hypertension, arteriosclerosis, arteriovenous fistula, ataxia,spinocerebellar degenerations, streptococcal myositis, structurallesions of the cerebellum, Subacute sclerosing panencephalitis, Syncope,syphilis of the cardiovascular system, systemic anaphalaxis, systemicinflammatory response syndrome, systemic onset juvenile rheumatoidarthritis, T-cell or FAB ALL, Telangiectasia, thromboangitis obliterans,transplants, trauma/hemorrhage, type III hypersensitivity reactions,type IV hypersensitivity, unstable angina, uremia, urosepsis, urticaria,valvular heart diseases, varicose veins, vasculitis, venous diseases,venous thrombosis, ventricular fibrillation, viral and fungalinfections, vital encephalitis/aseptic meningitis, vital-associatedhemaphagocytic syndrome, Wernicke-Korsakoff syndrome, Wilson's disease,xenograft rejection of any organ or tissue, heart transplant rejection,hemachromatosis, hemodialysis, hemolytic uremic syndrome/thrombolyticthrombocytopenic purpura, hemorrhage, idiopathic pulmonary fibrosis,antibody mediated cytotoxicity, Asthenia, infantile spinal muscularatrophy, inflammation of the aorta, influenza A, ionizing radiationexposure, iridocyclitis/uveitis/optic neuritis, juvenile spinal muscularatrophy, lymphoma, myeloma, leukaemia, malignant ascites, hematopoieticcancers, a diabetic condition such as insulin-dependent diabetesmellitus glaucoma, diabetic retinopathy or microangiopathy, sickle cellanaemia, chronic inflammation, glomerulonephritis, graft rejection, Lymedisease, von Hippel Lindau disease, pemphigoid, Paget's disease,fibrosis, sarcoidosis, cirrhosis, thyroiditis, hyperviscosity syndrome,Osler-Weber-Rendu disease, chronic occlusive pulmonary disease, asthmaor edema following burns, trauma, radiation, stroke, hypoxia, ischemia,ovarian hyperstimulation syndrome, post perfusion syndrome, post pumpsyndrome, post-MI cardiotomy syndrome, preeclampsia, menometrorrhagia,endometriosis, pulmonary hypertension, infantile hemangioma, orinfection by Herpes simplex, Herpes Zoster, human immunodeficiencyvirus, parapoxvirus, protozoa or toxoplasmosis, progressive supranucleopalsy, primary pulmonary hypertension, radiation therapy, Raynaud'sphenomenon, Raynaud's disease, Refsum's disease, regular narrow QRStachycardia, renovascular hypertension, restrictive cardiomyopathy,sarcoma, senile chorea, senile dementia of Lewy body type, shock, skinallograft, skin changes syndrome, ocular or macular edema, ocularneovascular disease, scleritis, radial keratotomy, uveitis, vitritis,myopia, optic pits, chronic retinal detachment, post-laser treatmentcomplications, conjunctivitis, Stargardt's disease, Eales disease,retinopathy, macular degeneration, restenosis, ischemia/reperfusioninjury, ischemic stroke, vascular occlusion, carotid obstructivedisease, ulcerative colitis, inflammatory bowel disease, diabetes,diabetes mellitus, insulin dependent diabetes mellitus, allergicdiseases, dermatitis scleroderma, graft versus host disease, organtransplant rejection (including but not limited to bone marrow and solidorgan rejection), acute or chronic immune disease associated with organtransplantation, sarcoidosis, disseminated intravascular coagulation,Kawasaki's disease, nephrotic syndrome, chronic fatigue syndrome,Wegener's granulomatosis, Henoch-Schoenlein purpurea, microscopicvasculitis of the kidneys, chronic active hepatitis, septic shock, toxicshock syndrome, sepsis syndrome, cachexia, infectious diseases,parasitic diseases, acquired immunodeficiency syndrome, acute transversemyelitis, Huntington's chorea, stroke, primary biliary cirrhosis,hemolytic anemia, malignancies, Addison's disease, idiopathic Addison'sdisease, sporadic, polyglandular deficiency type I and polyglandulardeficiency type II, Schmidt's syndrome, adult (acute) respiratorydistress syndrome, alopecia, alopecia areata, seronegative arthopathy,arthropathy, Reiter's disease, psoriatic arthropathy, ulcerative coliticarthropathy, enteropathic synovitis, chlamydia, yersinia and salmonellaassociated arthropathy, atheromatous disease/arteriosclerosis, atopicallergy, autoimmune bullous disease, pemphigus vulgaris, pemphigusfoliaceus, pemphigoid, linear IgA disease, autoimmune haemolyticanaemia, Coombs positive haemolytic anaemia, acquired perniciousanaemia, juvenile pernicious anaemia, peripheral vascular disorders,peritonitis, pernicious anemia, myalgic encephalitis/Royal Free Disease,chronic mucocutaneous candidiasis, giant cell arteritis, primarysclerosing hepatitis, cryptogenic autoimmune hepatitis, AcquiredImmunodeficiency Disease Syndrome, Acquired Immunodeficiency RelatedDiseases, Hepatitis A, Hepatitis B, Hepatitis C, His bundle arrythmias,HIV infection/HIV neuropathy, common varied immunodeficiency (commonvariable hypogammaglobulinaemia), dilated cardiomyopathy, femaleinfertility, ovarian failure, premature ovarian failure, fibrotic lungdisease, chronic wound healing, cryptogenic fibrosing alveolitis,post-inflammatory interstitial lung disease, interstitial pneumonitis,pneumocystis carinii pneumonia, pneumonia, connective tissue diseaseassociated interstitial lung disease, mixed connective tissue disease,associated lung disease, systemic sclerosis associated interstitial lungdisease, rheumatoid arthritis associated interstitial lung disease,systemic lupus erythematosus associated lung disease,dermatomyositis/polymyositis associated lung disease, Sjögren's diseaseassociated lung disease, ankylosing spondylitis associated lung disease,vasculitic diffuse lung disease, haemosiderosis associated lung disease,drug-induced interstitial lung disease, radiation fibrosis,bronchiolitis obliterans, chronic eosinophilic pneumonia, lymphocyticinfiltrative lung disease, postinfectious interstitial lung disease,gouty arthritis, autoimmune hepatitis, type-1 autoimmune hepatitis(classical autoimmune or lupoid hepatitis), type-2 autoimmune hepatitis(anti-LKM antibody hepatitis), autoimmune mediated hypoglycaemia, type Binsulin resistance with acanthosis nigricans, hypoparathyroidism, acuteimmune disease associated with organ transplantation, chronic immunedisease associated with organ transplantation, osteoarthritis, primarysclerosing cholangitis, psoriasis type 1, psoriasis type 2, idiopathicleucopaenia, autoimmune neutropaenia, renal disease NOS,glomerulonephritides, microscopic vasulitis of the kidneys, Lymedisease, discoid lupus erythematosus, male infertility idiopathic orNOS, sperm autoimmunity, multiple sclerosis (all subtypes), sympatheticophthalmia, pulmonary hypertension secondary to connective tissuedisease, acute and chronic pain (different forms of pain), Goodpasture'ssyndrome, pulmonary manifestation of polyarteritis nodosa, acuterheumatic fever, rheumatoid spondylitis, Still's disease, systemicsclerosis, Sjögren's syndrome, Takayasu's disease/arteritis, autoimmunethrombocytopaenia, toxicity, transplants, and diseases involvinginappropriate vascularization for example diabetic retinopathy,retinopathy of prematurity, choroidal neovascularization due toage-related macular degeneration, and infantile hemangiomas in humanbeings. In addition, such compounds may be useful in the treatment ofdisorders such as ascites, effusions, and exudates, including forexample macular edema, cerebral edema, acute lung injury, adultrespiratory distress syndrome (ARDS), proliferative disorders such asrestenosis, fibrotic disorders such as hepatic cirrhosis andatherosclerosis, mesangial cell proliferative disorders such as diabeticnephropathy, malignant nephrosclerosis, thrombotic microangiopathysyndromes, and glomerulopathies, myocardial angiogenesis, coronary andcerebral collaterals, ischemic limb angiogenesis, ischemia/reperfusioninjury, peptic ulcer Helicobacter related diseases, virally-inducedangiogenic disorders, preeclampsia, menometrorrhagia, cat scratch fever,rubeosis, neovascular glaucoma and retinopathies such as thoseassociated with diabetic retinopathy, retinopathy of prematurity, orage-related macular degeneration. In addition, these compounds can beused as active agents against hyperproliferative disorders such asthyroid hyperplasia (especially Grave's disease), and cysts (such ashypervascularity of ovarian stroma characteristic of polycystic ovariansyndrome (Stein-Leventhal syndrome) and polycystic kidney disease sincesuch diseases require a proliferation of blood vessel cells for growthand/or metastasis.

Compounds of Formula (I) or Formula (II) of the invention can be usedalone or in combination with an additional agent, e.g., a therapeuticagent, said additional agent being selected by the skilled artisan forits intended purpose. For example, the additional agent can be atherapeutic agent art-recognized as being useful to treat the disease orcondition being treated by the compound of the present invention. Theadditional agent also can be an agent that imparts a beneficialattribute to the therapeutic composition e.g., an agent that affects theviscosity of the composition.

It should further be understood that the combinations which are to beincluded within this invention are those combinations useful for theirintended purpose. The agents set forth below are illustrative forpurposes and not intended to be limited. The combinations, which arepart of this invention, can be the compounds of the present inventionand at least one additional agent selected from the lists below. Thecombination can also include more than one additional agent, e.g., twoor three additional agents if the combination is such that the formedcomposition can perform its intended function.

Preferred combinations are non-steroidal anti-inflammatory drug(s) alsoreferred to as NSAIDS which include drugs like ibuprofen. Otherpreferred combinations are corticosteroids including prednisolone; thewell known side-effects of steroid use can be reduced or even eliminatedby tapering the steroid dose required when treating patients incombination with the compounds of this invention. Non-limiting examplesof therapeutic agents for rheumatoid arthritis with which a compound ofFormula (I) or Formula (II) of the invention can be combined include thefollowing: cytokine suppressive anti-inflammatory drug(s) (CSAIDs);antibodies to or antagonists of other human cytokines or growth factors,for example, TNF, LT, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8,IL-12, IL-15, IL-16, IL-21, IL-23, interferons, EMAP-II, GM-CSF, FGF,and PDGF. Compounds of the invention can be combined with antibodies tocell surface molecules such as CD2, CD3, CD4, CD8, CD25, CD28, CD30,CD40, CD45, CD69, CD80 (B7.1), CD86 (B7.2), CD90, CTLA or their ligandsincluding CD154 (gp39 or CD40L).

Preferred combinations of therapeutic agents may interfere at differentpoints in the autoimmune and subsequent inflammatory cascade; preferredexamples include TNF antagonists like chimeric, humanized or human TNFantibodies, D2E7 (U.S. Pat. No. 6,090,382, HUMIRA™), CA2 (REMICADE™),SIMPONI™ (golimumab), CIMZIA™, ACTEMRA™, CDP 571, and soluble p55 or p75TNF receptors, derivatives, thereof, (p75TNFR1gG (ENBREL™) or p55TNFR1gG(Lenercept), and also TNFα converting enzyme (TACE) inhibitors;similarly IL-1 inhibitors (Interleukin-1-converting enzyme inhibitors,IL-1RA etc.) may be effective for the same reason. Other preferredcombinations include Interleukin 11. Yet other preferred combinationsare the other key players of the autoimmune response which may actparallel to, dependent on or in concert with IL-18 function; especiallypreferred are IL-12 antagonists including IL-12 antibodies or solubleIL-12 receptors, or IL-12 binding proteins. It has been shown that IL-12and IL-18 have overlapping but distinct functions and a combination ofantagonists to both may be most effective. Yet another preferredcombination is non-depleting anti-CD4 inhibitors. Yet other preferredcombinations include antagonists of the co-stimulatory pathway CD80(B7.1) or CD86 (B7.2) including antibodies, soluble receptors orantagonistic ligands.

A compound of Formula (I) or Formula (II) of the invention may also becombined with agents, such as methotrexate, 6-mercaptopurine,azathioprine sulphasalazine, mesalazine, olsalazinechloroquinine/hydroxychloroquine, pencillamine, aurothiomalate(intramuscular and oral), azathioprine, cochicine, corticosteroids(oral, inhaled and local injection), beta-2 adrenoreceptor agonists(salbutamol, terbutaline, salmeteral), xanthines (theophylline,aminophylline), cromoglycate, nedocromil, ketotifen, ipratropium andoxitropium, cyclosporin, FK506, rapamycin, mycophenolate mofetil,leflunomide, NSAIDs, for example, ibuprofen, corticosteroids such asprednisolone, phosphodiesterase inhibitors, adensosine agonists,antithrombotic agents, complement inhibitors, adrenergic agents, agentswhich interfere with signalling by proinflammatory cytokines such asTNFα, or IL-1 (e.g., NIK, IKK, p38 or MAP kinase inhibitors), IL-1βconverting enzyme inhibitors, T-cell signalling inhibitors such askinase inhibitors, metalloproteinase inhibitors, sulfasalazine,6-mercaptopurines, angiotensin converting enzyme inhibitors, solublecytokine receptors and derivatives thereof (e.g. soluble p55 or p75 TNFreceptors and the derivatives p75TNFRIgG (Enbrel™) and p55TNFRIgG(Lenercept), sIL-1RI, sIL-1RII, sIL-6R), antiinflammatory cytokines(e.g. IL-4, IL-10, IL-11, IL-13 and TGFβ), celecoxib, folic acid,hydroxychloroquine sulfate, rofecoxib, etanercept, infliximab, naproxen,valdecoxib, sulfasalazine, methylprednisolone, meloxicam,methylprednisolone acetate, gold sodium thiomalate, aspirin,triamcinolone acetonide, propoxyphene napsylate/apap, folate,nabumetone, diclofenac, piroxicam, etodolac, diclofenac sodium,oxaprozin, oxycodone HCl, hydrocodone bitartrate/apap, diclofenacsodium/misoprostol, fentanyl, anakinra, tramadol HCl, salsalate,sulindac, cyanocobalamin/fa/pyridoxine, acetaminophen, alendronatesodium, prednisolone, morphine sulfate, lidocaine hydrochloride,indomethacin, glucosamine sulf/chondroitin, amitriptyline HCl,sulfadiazine, oxycodone HCl/acetaminophen, olopatadine HCl misoprostol,naproxen sodium, omeprazole, cyclophosphamide, rituximab, IL-1 TRAP,MRA, CTLA4-IG, IL-18 BP, anti-IL-12, Anti-IL15, BIRB-796, SCIO-469,VX-702, AMG-548, VX-740, Roflumilast, IC-485, CDC-801, S1P1 agonists(such as FTY720), PKC family inhibitors (such as Ruboxistaurin orAEB-071) and Mesopram. Preferred combinations include methotrexate orleflunomide and in moderate or severe rheumatoid arthritis cases,cyclosporine and anti-TNF antibodies as noted above.

Non-limiting examples of therapeutic agents for inflammatory boweldisease with which a compound of Formula (I) or Formula (II) of theinvention can be combined include the following: budenoside; epidermalgrowth factor; corticosteroids; cyclosporin, sulfasalazine;aminosalicylates; 6-mercaptopurine; azathioprine; metronidazole;lipoxygenase inhibitors; mesalamine; olsalazine; balsalazide;antioxidants; thromboxane inhibitors; IL-1 receptor antagonists;anti-IL-1β monoclonal antibodies; anti-IL-6 monoclonal antibodies;growth factors; elastase inhibitors; pyridinyl-imidazole compounds;antibodies to or antagonists of other human cytokines or growth factors,for example, TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-15, IL-16,IL-23, EMAP-II, GM-CSF, FGF, and PDGF; cell surface molecules such asCD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD90 or theirligands; methotrexate; cyclosporine; FK506; rapamycin; mycophenolatemofetil; leflunomide; NSAIDs, for example, ibuprofen; corticosteroidssuch as prednisolone; phosphodiesterase inhibitors; adenosine agonists;antithrombotic agents; complement inhibitors; adrenergic agents; agentswhich interfere with signalling by proinflammatory cytokines such asTNFα (or IL-1 (e.g. NIK, IKK, or MAP kinase inhibitors); IL-1βconverting enzyme inhibitors; TNFα converting enzyme inhibitors; T-cellsignalling inhibitors such as kinase inhibitors; metalloproteinaseinhibitors; sulfasalazine; azathioprine; 6-mercaptopurines; angiotensinconverting enzyme inhibitors; soluble cytokine receptors and derivativesthereof (e.g. soluble p55 or p75 TNF receptors, sIL-1RI, sIL-1RII,sIL-6R) and antiinflammatory cytokines (e.g. IL-4, IL-10, IL-11, IL-13and TGFβ). Preferred examples of therapeutic agents for Crohn's diseasewith which a compound of Formula (I) or Formula (II) can be combinedinclude the following: TNF antagonists, for example, anti-TNFantibodies, D2E7 (U.S. Pat. No. 6,090,382, HUMIRA™), CA2 (REMICADE™),CDP 571, TNFR-Ig constructs, (p75TNFRIgG (ENBREL™) and p55TNFRIgG(LENERCEPT™) inhibitors and PDE4 inhibitors. A compound of Formula (I)or Formula (II) can be combined with corticosteroids, for example,budenoside and dexamethasone; sulfasalazine, 5-aminosalicylic acid;olsalazine; and agents which interfere with synthesis or action ofproinflammatory cytokines such as IL-1, for example, IL-1β convertingenzyme inhibitors and IL-1ra; T cell signaling inhibitors, for example,tyrosine kinase inhibitors; 6-mercaptopurine; IL-11; mesalamine;prednisone; azathioprine; mercaptopurine; infliximab; methylprednisolonesodium succinate; diphenoxylate/atrop sulfate; loperamide hydrochloride;methotrexate; omeprazole; folate; ciprofloxacin/dextrose-water;hydrocodone bitartrate/apap; tetracycline hydrochloride; fluocinonide;metronidazole; thimerosal/boric acid; cholestyramine/sucrose;ciprofloxacin hydrochloride; hyoscyamine sulfate; meperidinehydrochloride; midazolam hydrochloride; oxycodone HCl/acetaminophen;promethazine hydrochloride; sodium phosphate;sulfamethoxazole/trimethoprim; celecoxib; polycarbophil; propoxyphenenapsylate; hydrocortisone; multivitamins; balsalazide disodium; codeinephosphate/apap; colesevelam HCl; cyanocobalamin; folic acid;levofloxacin; methylprednisolone; natalizumab and interferon-gamma.

Non-limiting examples of therapeutic agents for multiple sclerosis withwhich a compound of Formula (I) or Formula (II) can be combined includethe following: corticosteroids; prednisolone; methylprednisolone;azathioprine; cyclophosphamide; cyclosporine; methotrexate;4-aminopyridine; tizanidine; interferon-β1a (AVONEX®; Biogen);interferon-β1b (BETASERON®; Chiron/Berlex); interferon α-n3) (InterferonSciences/Fujimoto), interferon-α (Alfa Wassermann/J&J), interferonβ1A-IF (Serono/Inhale Therapeutics), Peginterferon α 2b(Enzon/Schering-Plough), Copolymer 1 (Cop-1; COPAXONE®; TevaPharmaceutical Industries, Inc.); hyperbaric oxygen; intravenousimmunoglobulin; cladribine; antibodies to or antagonists of other humancytokines or growth factors and their receptors, for example, TNF, LT,IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-23, IL-15, IL-16, EMAP-II,GM-CSF, FGF, and PDGF. A compound of Formula (I) or Formula (II) can becombined with antibodies to cell surface molecules such as CD2, CD3,CD4, CD8, CD19, CD20, CD25, CD28, CD30, CD40, CD45, CD69, CD80, CD86,CD90 or their ligands. A compound of Formula (I) or Formula (II) mayalso be combined with agents such as methotrexate, cyclosporine, FK506,rapamycin, mycophenolate mofetil, leflunomide, an S1P1 agonist, NSAIDs,for example, ibuprofen, corticosteroids such as prednisolone,phosphodiesterase inhibitors, adensosine agonists, antithromboticagents, complement inhibitors, adrenergic agents, agents which interferewith signalling by proinflammatory cytokines such as TNFα, or IL-1(e.g., NIK, IKK, p38 or MAP kinase inhibitors), IL-1β converting enzymeinhibitors, TACE inhibitors, T-cell signaling inhibitors such as kinaseinhibitors, metalloproteinase inhibitors, sulfasalazine, azathioprine,6-mercaptopurines, angiotensin converting enzyme inhibitors, solublecytokine receptors and derivatives thereof (e.g. soluble p55 or p75 TNFreceptors, sIL-1RI, sIL-1RII, sIL-6R) and antiinflammatory cytokines(e.g. IL-4, IL-10, IL-13 and TGFβ).

Preferred examples of therapeutic agents for multiple sclerosis in whicha compound of Formula (I) or Formula (II) can be combined to includeinterferon-β, for example, IFNβ1a and IFNβ1b; copaxone, corticosteroids,caspase inhibitors, for example inhibitors of caspase-1, IL-1inhibitors, TNF inhibitors, and antibodies to CD40 ligand and CD80.

A compound of Formula (I) or Formula (II) may also be combined withagents, such as alemtuzumab, dronabinol, daclizumab, mitoxantrone,xaliproden hydrochloride, fampridine, glatiramer acetate, natalizumab,sinnabidol, α-immunokine NNSO3, ABR-215062, AnergiX.MS, chemokinereceptor antagonists, BBR-2778, calagualine, CPI-1189, LEM (liposomeencapsulated mitoxantrone), THC.CBD (cannabinoid agonist), MBP-8298,mesopram (PDE4 inhibitor), MNA-715, anti-IL-6 receptor antibody,neurovax, pirfenidone allotrap 1258 (RDP-1258), sTNF-R1, talampanel,teriflunomide, TGF-beta2, tiplimotide, VLA-4 antagonists (for example,TR-14035, VLA4 Ultrahaler, Antegran-ELAN/Biogen), interferon gammaantagonists and IL-4 agonists.

Non-limiting examples of therapeutic agents for ankylosing spondylitiswith which a compound of Formula (I) or Formula (II) can be combinedinclude the following: ibuprofen, diclofenac, misoprostol, naproxen,meloxicam, indomethacin, diclofenac, celecoxib, rofecoxib,sulfasalazine, methotrexate, azathioprine, minocyclin, prednisone, andanti-TNF antibodies, D2E7 (U.S. Pat. No. 6,090,382; HUMIRA™), CA2(REMICADE™), CDP 571, TNFR-Ig constructs, (p75TNFRIgG (ENBREL™) andp55TNFRIgG (LENERCEPT™)

Non-limiting examples of therapeutic agents for asthma with which acompound of Formula (I) or Formula (II) can be combined include thefollowing: albuterol, salmeterol/fluticasone, montelukast sodium,fluticasone propionate, budesonide, prednisone, salmeterol xinafoate,levalbuterol HCl, albuterol sulfate/ipratropium, prednisolone sodiumphosphate, triamcinolone acetonide, beclomethasone dipropionate,ipratropium bromide, azithromycin, pirbuterol acetate, prednisolone,theophylline anhydrous, methylprednisolone sodium succinate,clarithromycin, zafirlukast, formoterol fumarate, influenza virusvaccine, amoxicillin trihydrate, flunisolide, allergy injection,cromolyn sodium, fexofenadine hydrochloride, flunisolide/menthol,amoxicillin/clavulanate, levofloxacin, inhaler assist device,guaifenesin, dexamethasone sodium phosphate, moxifloxacin HCl,doxycycline hyclate, guaifenesin/d-methorphan,p-ephedrine/cod/chlorphenir, gatifloxacin, cetirizine hydrochloride,mometasone furoate, salmeterol xinafoate, benzonatate, cephalexin,pe/hydrocodone/chlorphenir, cetirizine HCl/pseudoephed,phenylephrine/cod/promethazine, codeine/promethazine, cefprozil,dexamethasone, guaifenesin/pseudoephedrine,chlorpheniramine/hydrocodone, nedocromil sodium, terbutaline sulfate,epinephrine, methylprednisolone, anti-IL-13 antibody, and metaproterenolsulfate.

Non-limiting examples of therapeutic agents for COPD with which acompound of Formula (I) or Formula (II) can be combined include thefollowing: albuterol sulfate/ipratropium, ipratropium bromide,salmeterol/fluticasone, albuterol, salmeterol xinafoate, fluticasonepropionate, prednisone, theophylline anhydrous, methylprednisolonesodium succinate, montelukast sodium, budesonide, formoterol fumarate,triamcinolone acetonide, levofloxacin, guaifenesin, azithromycin,beclomethasone dipropionate, levalbuterol HCl, flunisolide, ceftriaxonesodium, amoxicillin trihydrate, gatifloxacin, zafirlukast,amoxicillin/clavulanate, flunisolide/menthol,chlorpheniramine/hydrocodone, metaproterenol sulfate,methylprednisolone, mometasone furoate, p-ephedrine/cod/chlorphenir,pirbuterol acetate, p-ephedrine/loratadine, terbutaline sulfate,tiotropium bromide, (R,R)-formoterol, TgAAT, cilomilast and roflumilast.

Non-limiting examples of therapeutic agents for HCV with which acompound of Formula (I) or Formula (II) can be combined include thefollowing: Interferon-alpha-2α, Interferon-alpha-2β, Interferon-alphacon1, Interferon-alpha-n1, pegylated interferon-alpha-2α, pegylatedinterferon-alpha-2β, ribavirin, peginterferon alfa-2b+ribavirin,ursodeoxycholic acid, glycyrrhizic acid, thymalfasin, Maxamine, VX-497and any compounds that are used to treat HCV through intervention withthe following targets: HCV polymerase, HCV protease, HCV helicase, andHCV IRES (internal ribosome entry site).

Non-limiting examples of therapeutic agents for Idiopathic PulmonaryFibrosis with which a compound of Formula (I) or Formula (II) can becombined include the following: prednisone, azathioprine, albuterol,colchicine, albuterol sulfate, digoxin, gamma interferon,methylprednisolone sodium succinate, lorazepam, furosemide, lisinopril,nitroglycerin, spironolactone, cyclophosphamide, ipratropium bromide,actinomycin d, alteplase, fluticasone propionate, levofloxacin,metaproterenol sulfate, morphine sulfate, oxycodone HCl, potassiumchloride, triamcinolone acetonide, tacrolimus anhydrous, calcium,interferon-alpha, methotrexate, mycophenolate mofetil andinterferon-gamma-1β.

Non-limiting examples of therapeutic agents for myocardial infarctionwith which a compound of Formula (I) or Formula (II) can be combinedinclude the following: aspirin, nitroglycerin, metoprolol tartrate,enoxaparin sodium, heparin sodium, clopidogrel bisulfate, carvedilol,atenolol, morphine sulfate, metoprolol succinate, warfarin sodium,lisinopril, isosorbide mononitrate, digoxin, furosemide, simvastatin,ramipril, tenecteplase, enalapril maleate, torsemide, retavase, losartanpotassium, quinapril hydrochloride/magnesium carbonate, bumetanide,alteplase, enalaprilat, amiodarone hydrochloride, tirofiban HClm-hydrate, diltiazem hydrochloride, captopril, irbesartan, valsartan,propranolol hydrochloride, fosinopril sodium, lidocaine hydrochloride,eptifibatide, cefazolin sodium, atropine sulfate, aminocaproic acid,spironolactone, interferon, sotalol hydrochloride, potassium chloride,docusate sodium, dobutamine HCl, alprazolam, pravastatin sodium,atorvastatin calcium, midazolam hydrochloride, meperidine hydrochloride,isosorbide dinitrate, epinephrine, dopamine hydrochloride, bivalirudin,rosuvastatin, ezetimibe/simvastatin, avasimibe, and cariporide.

Non-limiting examples of therapeutic agents for psoriasis with which acompound of Formula (I) or Formula (II) can be combined include thefollowing: calcipotriene, clobetasol propionate, triamcinoloneacetonide, halobetasol propionate, tazarotene, methotrexate,fluocinonide, betamethasone diprop augmented, fluocinolone acetonide,acitretin, tar shampoo, betamethasone valerate, mometasone furoate,ketoconazole, pramoxine/fluocinolone, hydrocortisone valerate,flurandrenolide, urea, betamethasone, clobetasol propionate/emoll,fluticasone propionate, azithromycin, hydrocortisone, moisturizingformula, folic acid, desonide, pimecrolimus, coal tar, diflorasonediacetate, etanercept folate, lactic acid, methoxsalen, hc/bismuthsubgal/znox/resor, methylprednisolone acetate, prednisone, sunscreen,halcinonide, salicylic acid, anthralin, clocortolone pivalate, coalextract, coal tar/salicylic acid, coal tar/salicylic acid/sulfur,desoximetasone, diazepam, emollient, fluocinonide/emollient, mineraloil/castor oil/na lact, mineral oil/peanut oil, petroleum/isopropylmyristate, psoralen, salicylic acid, soap/tribromsalan, thimerosal/boricacid, celecoxib, infliximab, cyclosporine, alefacept, efalizumab,tacrolimus, pimecrolimus, PUVA, UVB, sulfasalazine, ABT-874 andustekinamab.

Non-limiting examples of therapeutic agents for psoriatic arthritis withwhich a compound of Formula (I) or Formula (II) can be combined includethe following: methotrexate, etanercept, rofecoxib, celecoxib, folicacid, sulfasalazine, naproxen, leflunomide, methylprednisolone acetate,indomethacin, hydroxychloroquine sulfate, prednisone, sulindac,betamethasone diprop augmented, infliximab, methotrexate, folate,triamcinolone acetonide, diclofenac, dimethylsulfoxide, piroxicam,diclofenac sodium, ketoprofen, meloxicam, methylprednisolone,nabumetone, tolmetin sodium, calcipotriene, cyclosporine, diclofenacsodium/misoprostol, fluocinonide, glucosamine sulfate, gold sodiumthiomalate, hydrocodone bitartrate/apap, ibuprofen, risedronate sodium,sulfadiazine, thioguanine, valdecoxib, alefacept, D2E7 (U.S. Pat. No.6,090,382, HUMIRA™), and efalizumab.

Non-limiting examples of therapeutic agents for restenosis with which acompound of Formula (I) or Formula (II) can be combined include thefollowing: sirolimus, paclitaxel, everolimus, tacrolimus, ABT-578, andacetaminophen.

Non-limiting examples of therapeutic agents for sciatica with which acompound of Formula (I) or Formula (II) can be combined include thefollowing: hydrocodone bitartrate/apap, rofecoxib, cyclobenzaprine HCl,methylprednisolone, naproxen, ibuprofen, oxycodone HCl/acetaminophen,celecoxib, valdecoxib, methylprednisolone acetate, prednisone, codeinephosphate/apap, tramadol hcl/acetaminophen, metaxalone, meloxicam,methocarbamol, lidocaine hydrochloride, diclofenac sodium, gabapentin,dexamethasone, carisoprodol, ketorolac tromethamine, indomethacin,acetaminophen, diazepam, nabumetone, oxycodone HCl, tizanidine HCl,diclofenac sodium/misoprostol, propoxyphene n-pap, asa/oxycod/oxycodoneter, ibuprofen/hydrocodone bit, tramadol HCl, etodolac, propoxypheneHCl, amitriptyline HCl, carisoprodol/codeine phos/asa, morphine sulfate,multivitamins, naproxen sodium, orphenadrine citrate, and temazepam.

Preferred examples of therapeutic agents for SLE (Lupus) with which acompound of Formula (I) or Formula (II) can be combined include thefollowing: NSAIDS, for example, diclofenac, naproxen, ibuprofen,piroxicam, indomethacin; COX2 inhibitors, for example, celecoxib,rofecoxib, valdecoxib; anti-malarials, for example, hydroxychloroquine;steroids, for example, prednisone, prednisolone, budenoside,dexamethasone; cytotoxics, for example, azathioprine, cyclophosphamide,mycophenolate mofetil, methotrexate; inhibitors of PDE4 or purinesynthesis inhibitor, for example Cellcept®. A compound of Formula (I) orFormula (II) may also be combined with agents such as sulfasalazine,5-aminosalicylic acid, olsalazine, Imuran® and agents which interferewith synthesis, production or action of proinflammatory cytokines suchas IL-1, for example, caspase inhibitors like IL-1β converting enzymeinhibitors and IL-1ra. A compound of Formula (I) or Formula (II) mayalso be used with T cell signaling inhibitors, for example, tyrosinekinase inhibitors; or molecules that target T cell activation molecules,for example, CTLA-4-IgG or anti-B7 family antibodies, anti-PD-1 familyantibodies. A compound of Formula (I) or Formula (II) can be combinedwith IL-11 or anti-cytokine antibodies, for example, fonotolizumab(anti-IFNg antibody), or anti-receptor receptor antibodies, for example,anti-IL-6 receptor antibody and antibodies to B-cell surface molecules.A compound of Formula (I) or Formula (II) may also be used with LJP 394(abetimus), agents that deplete or inactivate B-cells, for example,Rituximab (anti-CD20 antibody), lymphostat-B (anti-BlyS antibody), TNFantagonists, for example, anti-TNF antibodies, D2E7 (U.S. Pat. No.6,090,382; HUMIRA™), CA2 (REMICADE™), CDP 571, TNFR-Ig constructs,(p75TNFRIgG (ENBREL™) and p55TNFRIgG (LENERCEPT™).

In this invention, the following definitions are applicable:

A “therapeutically effective amount” is an amount of a compound ofFormula (I) or Formula (II) or a combination of two or more suchcompounds, which inhibits, totally or partially, the progression of thecondition or alleviates, at least partially, one or more symptoms of thecondition. A therapeutically effective amount can also be an amountwhich is prophylactically effective. The amount which is therapeuticallyeffective will depend upon the patient's size and gender, the conditionto be treated, the severity of the condition and the result sought. Fora given patient, a therapeutically effective amount can be determined bymethods known to those of skill in the art.

“Pharmaceutically acceptable salts” refers to those salts which retainthe biological effectiveness and properties of the free bases and whichare obtained by reaction with inorganic acids, for example, hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acidor organic acids such as sulfonic acid, carboxylic acid, organicphosphoric acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, citric acid, fumaric acid, maleic acid, succinicacid, benzoic acid, salicylic acid, lactic acid, tartaric acid (e.g. (+)or (−)-tartaric acid or mixtures thereof), amino acids (e.g. (+) or(−)-amino acids or mixtures thereof), and the like. These salts can beprepared by methods known to those skilled in the art.

Certain compounds of Formula (I) or Formula (II) which have acidicsubstituents may exist as salts with pharmaceutically acceptable bases.The present invention includes such salts. Examples of such saltsinclude sodium salts, potassium salts, lysine salts and arginine salts.These salts may be prepared by methods known to those skilled in theart.

Certain compounds of Formula (I) or Formula (II) and their salts mayexist in more than one crystal form and the present invention includeseach crystal form and mixtures thereof.

Certain compounds of Formula (I) or Formula (II) and their salts mayalso exist in the form of solvates, for example hydrates, and thepresent invention includes each solvate and mixtures thereof.

Certain compounds of Formula (I) or Formula (II) may contain one or morechiral centers, and exist in different optically active forms. Whencompounds of Formula (I) or Formula (II) contain one chiral center, thecompounds exist in two enantiomeric forms and the present inventionincludes both enantiomers and mixtures of enantiomers, such as racemicmixtures. The enantiomers may be resolved by methods known to thoseskilled in the art, for example by formation of diastereoisomeric saltswhich may be separated, for example, by crystallization; formation ofdiastereoisomeric derivatives or complexes which may be separated, forexample, by crystallization, gas-liquid or liquid chromatography;selective reaction of one enantiomer with an enantiomer-specificreagent, for example enzymatic esterification; or gas-liquid or liquidchromatography in a chiral environment, for example on a chiral supportfor example silica with a bound chiral ligand or in the presence of achiral solvent. It will be appreciated that where the desired enantiomeris converted into another chemical entity by one of the separationprocedures described above, a further step is required to liberate thedesired enantiomeric form. Alternatively, specific enantiomers may besynthesized by asymmetric synthesis using optically active reagents,substrates, catalysts or solvents, or by converting one enantiomer intothe other by asymmetric transformation.

When a compound of Formula (I) or Formula (II) contains more than onechiral center, it may exist in diastereoisomeric forms. Thediastereoisomeric compounds may be separated by methods known to thoseskilled in the art, for example chromatography or crystallization andthe individual enantiomers may be separated as described above. Thepresent invention includes each diastereoisomer of compounds of Formula(I) or Formula (II), and mixtures thereof.

Certain compounds of Formula (I) or Formula (II) may exist in differenttautomeric forms or as different geometric isomers, and the presentinvention includes each tautomer and/or geometric isomer of compounds ofFormula (I) or Formula (II) and mixtures thereof.

Certain compounds of Formula (I) or Formula (II) may exist in differentstable conformational forms which may be separable. Torsional asymmetrydue to restricted rotation about an asymmetric single bond, for examplebecause of steric hindrance or ring strain, may permit separation ofdifferent conformers. The present invention includes each conformationalisomer of compounds of Formula (I) or Formula (II) and mixtures thereof.

Certain compounds of Formula (I) or Formula (II) may exist inzwitterionic form and the present invention includes each zwitterionicform of compounds of Formula (I) or Formula (II) and mixtures thereof.

As used herein the term “pro-drug” refers to an agent which is convertedinto the parent drug in vivo by some physiological chemical process(e.g., a prodrug on being brought to the physiological pH is convertedto the desired drug form). Pro-drugs are often useful because, in somesituations, they may be easier to administer than the parent drug. Theymay, for instance, be bioavailable by oral administration whereas theparent drug is not. The pro-drug may also have improved solubility inpharmacological compositions over the parent drug. An example, withoutlimitation, of a pro-drug would be a compound of the present inventionwherein it is administered as an ester (the “pro-drug”) to facilitatetransmittal across a cell membrane where water solubility is notbeneficial, but then it is metabolically hydrolyzed to the carboxylicacid once inside the cell where water solubility is beneficial.

Pro-drugs have many useful properties. For example, a pro-drug may bemore water soluble than the ultimate drug, thereby facilitatingintravenous administration of the drug. A pro-drug may also have ahigher level of oral bioavailability than the ultimate drug. Afteradministration, the prodrug is enzymatically or chemically cleaved todeliver the ultimate drug in the blood or tissue.

Exemplary pro-drugs upon cleavage release the corresponding free acid,and such hydrolyzable ester-forming residues of the compounds of thisinvention include but are not limited to carboxylic acid substituentswherein the free hydrogen is replaced by (C₁-C₄)alkyl,(C₁-C₁₂)alkanoyloxymethyl, (C₄-C₉)1-(alkanoyloxy)ethyl,1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N—(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylamino ethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)-alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl.

Other exemplary pro-drugs release an alcohol of Formula (I) or Formula(II) wherein the free hydrogen of the hydroxyl substituent (e.g., Rgroup contains hydroxyl) is replaced by (C₁-C₆)alkanoyloxymethyl,1-((C₁-C₆)alkanoyloxy)ethyl, 1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl,(C₁-C₁₂alkoxycarbonyloxymethyl, N—(C₁-C₆)alkoxycarbonylamino-methyl,succinoyl, (C₁-C₆)alkanoyl, α-amino(C₁-C₄)alkanoyl, arylactyl andα-aminoacyl, or α-aminoacyl-α-aminoacyl wherein said α-aminoacylmoieties are independently any of the naturally occurring L-amino acidsfound in proteins, P(O)(OH)₂, —P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (theradical resulting from detachment of the hydroxyl of the hemiacetal of acarbohydrate).

As used herein, the term “bridged (C₅-C₁₂) cycloalkyl group” means asaturated or unsaturated, bicyclic or polycyclic bridged hydrocarbongroup having two or three C₃-C₁₀ cycloalkyl rings. Non bridgedcycloalkyls are excluded. Bridged cyclic hydrocarbon may include, suchas bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl,bicyclo[3.2.1]octyl, bicyclo[4.3.1]decyl, bicyclo[3.3.1]nonyl, bornyl,bornenyl, norbornyl, norbornenyl, 6,6-dimethylbicyclo[3.1.1]heptyl,tricyclobutyl, and adamantyl.

As used herein the term “bridged (C₂-C₁₀) heterocyclyl” means bicyclicor polycyclic aza-bridged hydrocarbon groups and may includeazanorbornyl, quinuclidinyl, isoquinuclidinyl, tropanyl,azabicyclo[3.2.1]octanyl, azabicyclo[2.2.1]heptanyl,2-azabicyclo[3.2.1]octanyl, azabicyclo[3.2.1]octanyl,azabicyclo[3.2.2]nonanyl, azabicyclo[3.3.0]nonanyl, andazabicyclo[3.3.1]nonanyl.

The term “heterocyclic”, “heterocyclyl” or “heterocyclylene”, as usedherein, include non-aromatic, ring systems, including, but not limitedto, monocyclic, bicyclic, tricyclic and spirocyclic rings, which can becompletely saturated or which can contain one or more units ofunsaturation, for the avoidance of doubt, the degree of unsaturationdoes not result in an aromatic ring system) and have 5 to 12 atomsincluding at least one heteroatom, such as nitrogen, oxygen, or sulfur.For purposes of exemplification, which should not be construed aslimiting the scope of this invention, the following are examples ofheterocyclic rings: azepinyl, azetidinyl, indolinyl, isoindolinyl,morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, quinuclidinyl,thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl,tetrahydroindolyl, thiomorpholinyl and tropanyl.

The term “heteroaryl” or “heteroarylene” as used herein, includearomatic ring systems, including, but not limited to, monocyclic,bicyclic and tricyclic rings, and have 5 to 12 atoms including at leastone heteroatom, such as nitrogen, oxygen, or sulfur. For purposes ofexemplification, which should not be construed as limiting the scope ofthis invention: azaindolyl, benzo[b]thienyl, benzimidazolyl,benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl,benzoxadiazolyl, furanyl, imidazolyl, imidazopyridinyl, indolyl,indazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, purinyl,pyranyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolyl,pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl, quinolinyl,quinazolinyl, triazolyl, thiazolyl, thiophenyl, tetrazolyl,thiadiazolyl, or thienyl.

An “heterocycloalkyl” group, as used herein, is a heterocyclic groupthat is linked to a compound by an aliphatic group having from one toabout eight carbon atoms. For example, a heterocycloalkyl group is amorpholinomethyl group.

As used herein, “alkyl”, “alkylene” or notations such as “(C₁-C₈)”include straight chained or branched hydrocarbons which are completelysaturated. Examples of alkyls are methyl, ethyl, propyl, isopropyl,butyl, pentyl, hexyl and isomers thereof. As used herein, “alkenyl”,“alkenylene”, “alkynylene” and “alkynyl” means C₂-C₈ and includesstraight chained or branched hydrocarbons which contain one or moreunits of unsaturation, one or more double bonds for alkenyl and one ormore triple bonds for alkynyl.

As used herein, “aromatic” groups (or “aryl” or “arylene” groups)include aromatic carbocyclic ring systems (e.g. phenyl) and fusedpolycyclic aromatic ring systems (e.g. naphthyl, biphenyl and1,2,3,4-tetrahydronaphthyl).

As used herein, “cycloalkyl” or “cycloalkylene” means C₃-C₁₂ monocyclicor multicyclic (e.g., bicyclic, tricyclic, spirocyclic, etc.)hydrocarbons that is completely saturated or has one or more unsaturatedbonds but does not amount to an aromatic group. Examples of a cycloalkylgroup are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,cyclohexyl and cyclohexenyl.

As used herein, many moieties or substituents are termed as being either“substituted” or “optionally substituted”. When a moiety is modified byone of these terms, unless otherwise noted, it denotes that any portionof the moiety that is known to one skilled in the art as being availablefor substitution can be substituted, which includes one or moresubstituents, where if more than one substituent then each substituentis independently selected. Such means for substitution are well-known inthe art and/or taught by the instant disclosure. For purposes ofexemplification, which should not be construed as limiting the scope ofthis invention, some examples of groups that are substituents are:(C₁-C₈)alkyl groups, (C₂-C₈)alkenyl groups, (C₂-C₈)alkynyl groups,(C₃-C₁₀)cycloalkyl groups, halogen (F, Cl, Br or I), halogenated(C₁-C₈)alkyl groups (for example but not limited to CF₃),—O—(C₁-C₈)alkyl groups, —OH, —S—(C₁-C₈)alkyl groups, —SH,—NH(C₁-C₈)alkyl groups, —N((C₁-C₈)alkyl)₂ groups, —NH₂, —C(O)NH₂,—C(O)NH(C₁-C₈)alkyl groups, —C(O)N((C₁-C₈)alkyl)₂, —NHC(O)H, —NHC(O)(C₁-C₈)alkyl groups, —NHC(O) (C₃-C₈)cycloalkyl groups,—N((C₁-C₈)alkyl)C(O)H, —N((C₁-C₈)alkyl)C(O)(C₁-C₈)alkyl groups,—NHC(O)NH₂, —NHC(O)NH(C₁-C₈)alkyl groups, —N((C₁-C₈)alkyl)C(O)NH₂groups, —NHC(O)N((C₁-C₈)alkyl)₂ groups,—N((C₁-C₈)alkyl)C(O)N((C₁-C₈)alkyl)₂ groups,—N((C₁-C₈)alkyl)C(O)NH((C₁-C₈)alkyl), —C(O)H, —C(O)(C₁-C₈)alkyl groups,—CN, —NO₂, —S(O)(C₁-C₈)alkyl groups, —S(O)₂(C₁-C₈)alkyl groups,—S(O)₂N((C₁-C₈)alkyl)₂ groups, —S(O)₂NH(C₁-C₈)alkyl groups,—S(O)₂NH(C₃-C₈)cycloalkyl groups, —S(O)₂NH₂ groups, —NHS(O)₂(C₁-C₈)alkylgroups, —N((C₁-C₈)alkyl)S(O)₂(C₁-C₈)alkyl groups,—(C₁-C₈)alkyl-O—(C₁-C₈)alkyl groups, —O—(C₁-C₈)alkyl-O—(C₁-C₈)alkylgroups, —C(O)OH, —C(O)O(C₁-C₈)alkyl groups, NHOH, NHO(C₁-C₈)alkylgroups, —O-halogenated (C₁-C₈)alkyl groups (for example but not limitedto —OCF₃), —S(O)₂-halogenated (C₁-C₈)alkyl groups (for example but notlimited to S(O)₂CF₃), —S-halogenated (C₁-C₈)alkyl groups (for examplebut not limited to SCF₃), —(C₁-C₆) heterocycle (for example but notlimited to pyrrolidine, tetrahydrofuran, pyran or morpholine), —(C₁-C₆)heteroaryl (for example but not limited to tetrazole, imidazole, furan,pyrazine or pyrazole), -phenyl, —NHC(O)O—(C₁-C₆)alkyl groups,—N((C₁-C₆)alkyl)C(O)O—(C₁-C₆)alkyl groups, —C(═NH)— (C₁-C₆)alkyl groups,—C(═NOH)—(C₁-C₆)alkyl groups, or —C(═N—O—(C₁-C₆)alkyl)-(C₁-C₆)alkylgroups.

in Formula (I) represents an aromatic ring.

One or more compounds of this invention can be administered to a humanpatient by themselves or in pharmaceutical compositions where they aremixed with biologically suitable carriers or excipient(s) at doses totreat or ameliorate a disease or condition as described herein. Mixturesof these compounds can also be administered to the patient as a simplemixture or in suitable formulated pharmaceutical compositions. Atherapeutically effective dose refers to that amount of the compound orcompounds sufficient to result in the prevention or attenuation of adisease or condition as described herein. Techniques for formulation andadministration of the compounds of the instant application may be foundin references well known to one of ordinary skill in the art, such as“Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, Pa.,latest edition.

Suitable routes of administration may, for example, include oral,eyedrop, rectal, transmucosal, topical, or intestinal administration;parenteral delivery, including intramuscular, subcutaneous,intramedullary injections, as well as intrathecal, directintraventricular, intravenous, intraperitoneal, intranasal, orintraocular injections.

Alternatively, one may administer the compound in a local rather than asystemic manner, for example, via injection of the compound directlyinto an edematous site, often in a depot or sustained releaseformulation.

Furthermore, one may administer the drug in a targeted drug deliverysystem, for example, in a liposome coated with endothelial cell-specificantibody.

The pharmaceutical compositions of the present invention may bemanufactured in a manner that is itself known, e.g., by means ofconventional mixing, dissolving, granulating, dragee-making, levigating,emulsifying, encapsulating, entrapping or lyophilizing processes.

Pharmaceutical compositions for use in accordance with the presentinvention thus may be formulated in a conventional manner using one ormore physiologically acceptable carriers comprising excipients andauxiliaries which facilitate processing of the active compounds intopreparations which can be used pharmaceutically. Proper formulation isdependent upon the route of administration chosen.

For injection, the agents of the invention may be formulated in aqueoussolutions, preferably in physiologically compatible buffers such asHanks' solution, Ringer's solution, or physiological saline buffer. Fortransmucosal administration, penetrants appropriate to the barrier to bepermeated are used in the formulation. Such penetrants are generallyknown in the art.

For oral administration, the compounds can be formulated readily bycombining the active compounds with pharmaceutically acceptable carrierswell known in the art. Such carriers enable the compounds of theinvention to be formulated as tablets, pills, dragees, capsules,liquids, gels, syrups, slurries, suspensions and the like, for oralingestion by a patient to be treated. Pharmaceutical preparations fororal use can be obtained by combining the active compound with a solidexcipient, optionally grinding a resulting mixture, and processing themixture of granules, after adding suitable auxiliaries, if desired, toobtain tablets or dragee cores. Suitable excipients are, in particular,fillers such as sugars, including lactose, sucrose, mannitol, orsorbitol; cellulose preparations such as, for example, maize starch,wheat starch, rice starch, potato starch, gelatin, gum tragacanth,methyl cellulose, hydroxypropylmethyl-cellulose, sodiumcarboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired,disintegrating agents may be added, such as the cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodiumalginate.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

Pharmaceutical preparations that can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added. All formulations fororal administration should be in dosages suitable for suchadministration.

For buccal administration, the compositions may take the form of tabletsor lozenges formulated in conventional manner.

For administration by inhalation, the compounds for use according to thepresent invention are conveniently delivered in the form of an aerosolspray presentation from pressurized packs or a nebuliser, with the useof a suitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of pressurized aerosol the dosage unitmay be determined by providing a valve to deliver a metered amount.Capsules and cartridges of e.g. gelatin for use in an inhaler orinsufflator may be formulated containing a powder mix of the compoundand a suitable powder base such as lactose or starch.

The compounds can be formulated for parenteral administration byinjection, e.g. bolus injection or continuous infusion. Formulations forinjection may be presented in unit dosage form, e.g. in ampoules or inmulti-dose containers, with an added preservative. The compositions maytake such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents.

Pharmaceutical formulations for parenteral administration includeaqueous solutions of the active compounds in water-soluble form.Additionally, suspensions of the active compounds may be prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles include fatty oils such as sesame oil, or synthetic fatty acidesters, such as ethyl oleate or triglycerides, or liposomes. Aqueousinjection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.

Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,before use.

The compounds may also be formulated in rectal compositions such assuppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter or other glycerides.

In addition to the formulations described previously, the compounds mayalso be formulated as a depot preparation. Such long acting formulationsmay be administered by implantation (for example subcutaneously orintramuscularly or by intramuscular injection). Thus, for example, thecompounds may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

An example of a pharmaceutical carrier for the hydrophobic compounds ofthe invention is a cosolvent system comprising benzyl alcohol, anonpolar surfactant, a water-miscible organic polymer, and an aqueousphase. The cosolvent system may be the VPD co-solvent system. VPD is asolution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactantpolysorbate 80, and 65% w/v polyethylene glycol 300, made up to volumein absolute ethanol. The VPD co-solvent system (VPD:5W) consists of VPDdiluted 1:1 with a 5% dextrose in water solution. This co-solvent systemdissolves hydrophobic compounds well, and itself produces low toxicityupon systemic administration. Naturally, the proportions of a co-solventsystem may be varied considerably without destroying its solubility andtoxicity characteristics. Furthermore, the identity of the co-solventcomponents may be varied: for example, other low-toxicity nonpolarsurfactants may be used instead of polysorbate 80; the fraction size ofpolyethylene glycol may be varied; other biocompatible polymers mayreplace polyethylene glycol, e.g. polyvinyl pyrrolidone; and othersugars or polysaccharides may substitute for dextrose.

Alternatively, other delivery systems for hydrophobic pharmaceuticalcompounds may be employed. Liposomes and emulsions are well knownexamples of delivery vehicles or carriers for hydrophobic drugs. Certainorganic solvents such as dimethylsulfoxide also may be employed,although usually at the cost of greater toxicity. Additionally, thecompounds may be delivered using a sustained-release system, such assemipermeable matrices of solid hydrophobic polymers containing thetherapeutic agent. Various sustained-release materials have beenestablished and are well known by those skilled in the art.Sustained-release capsules may, depending on their chemical nature,release the compounds for a few hours up to over several days. Dependingon the chemical nature and the biological stability of the therapeuticreagent, additional strategies for protein stabilization may beemployed.

The pharmaceutical compositions also may comprise suitable solid or gelphase carriers or excipients. Examples of such carriers or excipientsinclude but are not limited to calcium carbonate, calcium phosphate,various sugars, starches, cellulose derivatives, gelatin, and polymerssuch as polyethylene glycols.

Many of the compounds of the invention may be provided as salts withpharmaceutically compatible counterions. Pharmaceutically compatiblesalts may be formed with many acids, including but not limited tohydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc.Salts tend to be more soluble in aqueous or other protonic solvents thanare the corresponding free base forms.

Pharmaceutical compositions suitable for use in the present inventioninclude compositions wherein the active ingredients are contained in aneffective amount to achieve its intended purpose. More specifically, atherapeutically effective amount means an amount effective to preventdevelopment of or to alleviate the existing symptoms of the subjectbeing treated. Determination of the effective amounts is well within thecapability of those skilled in the art.

For any compound used in a method of the present invention, thetherapeutically effective dose can be estimated initially from cellularassays. For example, a dose can be formulated in cellular and animalmodels to achieve a circulating concentration range that includes theIC₅₀ as determined in cellular assays (i.e., the concentration of thetest compound which achieves a half-maximal inhibition of a givenprotein kinase activity). In some cases it is appropriate to determinethe IC₅₀ in the presence of 3 to 5% serum albumin since such adetermination approximates the binding effects of plasma protein on thecompound. Such information can be used to more accurately determineuseful doses in humans. Further, the most preferred compounds forsystemic administration effectively inhibit protein kinase signaling inintact cells at levels that are safely achievable in plasma.

A therapeutically effective dose refers to that amount of the compoundthat results in amelioration of symptoms in a patient. Toxicity andtherapeutic efficacy of such compounds can be determined by standardpharmaceutical procedures in cell cultures or experimental animals,e.g., for determining the maximum tolerated dose (MTD) and the ED₅₀(effective dose for 50% maximal response). The dose ratio between toxicand therapeutic effects is the therapeutic index and it can be expressedas the ratio between MTD and ED₅₀. Compounds which exhibit hightherapeutic indices are preferred. The data obtained from these cellculture assays and animal studies can be used in formulating a range ofdosage for use in humans. The dosage of such compounds lies preferablywithin a range of circulating concentrations that include the ED₅₀ withlittle or no toxicity. The dosage may vary within this range dependingupon the dosage form employed and the route of administration utilized.The exact formulation, route of administration and dosage can be chosenby the individual physician in view of the patient's condition (see e.g.Fingl et al., 1975, in “The Pharmacological Basis of Therapeutics”, Ch.1 p. 1). In the treatment of crises, the administration of an acutebolus or an infusion approaching the MTD may be required to obtain arapid response.

Dosage amount and interval may be adjusted individually to provideplasma levels of the active moiety which are sufficient to maintain thekinase modulating effects, or minimal effective concentration (MEC). TheMEC will vary for each compound but can be estimated from in vitro data;e.g. the concentration necessary to achieve 50-90% inhibition of proteinkinase using the assays described herein. Dosages necessary to achievethe MEC will depend on individual characteristics and route ofadministration. However, HPLC assays or bioassays can be used todetermine plasma concentrations.

Dosage intervals can also be determined using the MEC value. Compoundsshould be administered using a regimen which maintains plasma levelsabove the MEC for 10-90% of the time, preferably between 30-90% and mostpreferably between 50-90% until the desired amelioration of symptoms isachieved. In cases of local administration or selective uptake, theeffective local concentration of the drug may not be related to plasmaconcentration.

The amount of composition administered will, of course, be dependent onthe subject being treated, on the subject's weight, the severity of theaffliction, the manner of administration and the judgment of theprescribing physician.

The compositions may, if desired, be presented in a pack or dispenserdevice which may contain one or more unit dosage forms containing theactive ingredient. The pack may for example comprise metal or plasticfoil, such as a blister pack. The pack or dispenser device may beaccompanied by instructions for administration. Compositions comprisinga compound of the invention formulated in a compatible pharmaceuticalcarrier may also be prepared, placed in an appropriate container, andlabelled for treatment of an indicated condition.

In some formulations it may be beneficial to use the compounds of thepresent invention in the form of particles of very small size, forexample as obtained by fluid energy milling.

The use of compounds of the present invention in the manufacture ofpharmaceutical compositions is illustrated by the following description.In this description the term “active compound” denotes any compound ofthe invention but particularly any compound which is the final productof one of the following Examples.

a) Capsules

In the preparation of capsules, 10 parts by weight of active compoundand 240 parts by weight of lactose can be de-aggregated and blended. Themixture can be filled into hard gelatin capsules, each capsulecontaining a unit dose or part of a unit dose of active compound.

b) Tablets

Tablets can be prepared, for example, from the following ingredients.

Parts by weight Active compound 10 Lactose 190 Maize starch 22Polyvinylpyrrolidone 10 Magnesium stearate 3

The active compound, the lactose and some of the starch can bede-aggregated, blended and the resulting mixture can be granulated witha solution of the polyvinylpyrrolidone in ethanol. The dry granulate canbe blended with the magnesium stearate and the rest of the starch. Themixture is then compressed in a tabletting machine to give tablets eachcontaining a unit dose or a part of a unit dose of active compound.

c) Enteric Coated Tablets

Tablets can be prepared by the method described in (b) above. Thetablets can be enteric coated in a conventional manner using a solutionof 20% cellulose acetate phthalate and 3% diethyl phthalate inethanol:dichloromethane (1:1).

d) Suppositories

In the preparation of suppositories, for example, 100 parts by weight ofactive compound can be incorporated in 1300 parts by weight oftriglyceride suppository base and the mixture formed into suppositorieseach containing a therapeutically effective amount of active ingredient.

In the compositions of the present invention the active compound may, ifdesired, be associated with other compatible pharmacologically activeingredients. For example, the compounds of this invention can beadministered in combination with another therapeutic agent that is knownto treat a disease or condition described herein. For example, with oneor more additional pharmaceutical agents that inhibit or prevent theproduction of VEGF or angiopoietins, attenuate intracellular responsesto VEGF or angiopoietins, block intracellular signal transduction,inhibit vascular hyperpermeability, reduce inflammation, or inhibit orprevent the formation of edema or neovascularization. The compounds ofthe invention can be administered prior to, subsequent to orsimultaneously with the additional pharmaceutical agent, whichevercourse of administration is appropriate. The additional pharmaceuticalagents include, but are not limited to, anti-edemic steroids, NSAIDS,ras inhibitors, anti-TNF agents, anti-IL1 agents, antihistamines,PAF-antagonists, COX-1 inhibitors, COX-2 inhibitors, NO synthaseinhibitors, Akt/PTB inhibitors, IGF-1R inhibitors, PKC inhibitors, PI3kinase inhibitors, calcineurin inhibitors and immunosuppressants. Thecompounds of the invention and the additional pharmaceutical agents acteither additively or synergistically. Thus, the administration of such acombination of substances that inhibit angiogenesis, vascularhyperpermeability and/or inhibit the formation of edema can providegreater relief from the deletrious effects of a hyperproliferativedisorder, angiogenesis, vascular hyperpermeability or edema than theadministration of either substance alone. In the treatment of malignantdisorders combinations with antiproliferative or cytotoxicchemotherapies or radiation are included in the scope of the presentinvention.

The present invention also comprises the use of a compound of Formula(I) or Formula (II) as a medicament.

A further aspect of the present invention provides the use of a compoundof Formula (I) or Formula (II) or a salt thereof in the manufacture of amedicament for treating vascular hyperpermeability,angiogenesis-dependent disorders, proliferative diseases and/ordisorders of the immune system in mammals, particularly human beings.

The present invention also provides a method of treating vascularhyperpermeability, inappropriate neovascularization, proliferativediseases and/or disorders of the immune system which comprises theadministration of a therapeutically effective amount of a compound ofFormula (I) or Formula (II) to a mammal, particularly a human being, inneed thereof.

Abbreviations

-   aa Amino acids-   Ac₂O Acetic anhydride-   AcOH Glacial acetic acid-   ATP Adenosine triphosphate-   b.p. Boiling point-   BArF tetrakis-[3,5-bis(trifluoromethyl)phenyl]borate-   Bn Benzyl-   Boc t-Butoxycarbonyl-   BOP-Cl Bis(2-oxo-3-oxazolidinyl)phosphonic chloride-   BSA Bovine serum albumin-   BuOH Butanol-   CAN Ceric ammonium nitrate-   Cbz Carboxybenzyl-   CDI 1,1′-Carbonyldiimidazole-   COD 1,5-Cyclooctadiene-   concd Concentrated-   CT Computed tomography-   cym p-cymene (4-isopropyltoluene)-   CyPFt-Bu    1-Dicyclohexylphosphino-2-di-tert-butylphosphinoethylferrocene-   d Doublet-   DAST Diethylaminosulfur trifluoride-   dba Dibenzylideneacetone-   DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene-   DCC Dicyclohexylcarbodiimide-   DCE Dichloroethane-   DCM Dichloromethane (methylene chloride)-   dd Doublet of doublets-   DEAD Diethyl azodicarboxylate-   DIBAL-H Diisobutylaluminium hydride-   DIAD Diisopropyl azodicarboxylate-   DIEA N,N-Diisopropylethylamine-   DMA Dimethylacetamide-   DMAP N,N-Dimethylaminopyridine-   DME 1,2-Dimethoxyethane-   DMEM Dulbecco's Modified Eagle Medium-   DMF N,N-Dimethylformamide-   DMS Dimethylsulfide-   DMSO Dimethyl sulfoxide-   DNP-HSA Dinitrophenyl-human serum albumin-   DPPA Diphenyl phosphorazidate-   dppf 1,1′-Bis(diphenylphosphino)ferrocene-   dr Diastereomeric ratio-   DTT Dithiothreitol-   EDC.HCl N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride-   EDTA Ethylene diamine tetraacetic acid-   EGTA Ethylene glycol tetraacetic acid-   equiv Equivalent(s)-   er Enantiomeric ratio-   Et₂NH Diethylamine-   EtOAc Ethyl acetate-   Et₂O Diethyl ether-   EtOH Ethanol-   FBS Fetal bovine serum-   FLAG DYKDDDDK peptide sequence-   g Gram(s)-   GST Glutathione S-transferase-   h Hour(s)-   H₂SO₄ Sulfuric acid-   HATU 0-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HEPES N-2-Hydroxyethylpiperazine-N′-2-ethanesulfonic acid-   HOBt Hydroxybenzotriazole-   HPLC High-pressure liquid chromatography-   Hz Hertz-   IBCF Isobutylchloroformate-   i.d. Intradermal-   IFA Incomplete Freunds Adjuvant-   IPA Isopropyl alcohol-   KHMDS Potassium hexamethyldisilazane-   LAH Lithium aluminum hydride-   LC Liquid chromatography-   LDA Lithium diisopropylamide-   LHMDS Lithium bis(trimethylsilyl)amide-   LiBH₄ Lithium borohydride-   LiOH Lithium hydroxide-   m Multiplet-   M Molar-   m-CPBA meta-Chloroperbenzoic acid-   MeCN Acetonitrile-   MeOH Methyl alcohol-   min Minute(s)-   mL Milliliter(s)-   mmHg Millimeters of mercury-   mmol Millimole-   MOPS 3-(N-morpholino)-propanesulfonic acid-   MOPSO 3-(N-morpholino)-2-hydroxypropanesulfonic acid-   MS Mass spectrometry-   MTBE Methyl tert-butyl ether-   n- Normal (nonbranched)-   n-BuLi n-Butyl lithium-   N Normal-   NaHMDS Sodium bis(trimethylsilyl)amide-   NaOAc Sodium acetate-   Na(OAc)₃BH Sodium triacetoxyborohydride-   NaOt-Bu Sodium tert-butoxide-   NBS N-Bromosuccinimide-   NCS N-Chlorosuccinimide-   ND Not determined-   NH₄OAc Ammonium acetate-   NIS N-Iodosuccinimide-   NMM N-Methylmorpholine-   NMP N-Methylpyrrolidinone-   NMR Nuclear magnetic resonance-   OD Optical density-   or Optical rotation-   OVA Ovalbumin-   p- Para-   PBS Phosphate buffered saline-   PFPAA 2,2,3,3,3-Pentafluoropropanoic Anhydride-   pH −log [H⁺]-   PMB p-Methoxybenzyl-   pNAG Nitrophenyl-N-acetyl-β-D-glucosaminide-   P(n-Bu)₃ tri-n-Butyl phosphine-   POCl₃ Phosphorus oxychloride-   PPh₃ Triphenylphosphine-   ppm Parts per million-   PrOH Propanol-   psi Pounds per square inch-   rcf Relative centrifugal force-   RP-HPLC Reverse-phase high-pressure liquid chromatography-   R_(t) Retention time-   rt Room temperature-   s Singlet-   SEM 2-(Trimethylsilyl)ethoxymethyl-   SEM-Cl 2-(Trimethylsilyl)ethoxymethyl chloride-   SFC Supercritical Fluid Chromatography-   SLM Standard liters per minute-   t Triplet-   t- Tertiary-   TBDMS tert-Butyldimethylsilyl-   TBDMSCl tert-Butyldimethylsilyl chloride-   TBAB Tetra-n-butylammonium bromide-   TBAF Tetra-n-butylammonium fluoride-   TBAI Tetra-n-butylammonium iodide-   TEA Triethylamine-   tert- Tertiary-   TFA Trifluoroacetic acid-   TFAA Trifluoracetic anhydride-   THF Tetrahydrofuran-   TIPS Triisopropylsilyl-   TLC Thin layer chromatography-   TMA Trimethyl aluminium-   TMAD N,N,N′,N′-Tetramethylazodicarbonamide or    1,1′-azobis(N,N-dimethylformamide) or diamide [Sigma®]-   TMOF Trimethyl orthoformate-   TMS Trimethylsilyl-   TPP 2,4,6-Tripropyl-[1,3,5,2,4,6]trioxatriphosphinane 2,4,6-trioxide-   TsCl para-Toluenesulfonyl chloride-   TsOH para-Toluenesulfonic acid-   USP United States Pharmacopeia-   UV Ultraviolet-   wt % Weight percent-   w/v Weight/volume

Assays

In Vitro Jak1 Kinase Activity Measured by Time-Resolved FluorescenceResonance Energy Transfer (trFRET)

Varying concentrations of inhibitor were added to an assay wellcontaining: Jak1 enzyme (aa 845-1142; expressed in SF9 cells as a GSTfusion and purified by glutathione affinity chromatography; 4 nM),peptide substrate (biotin-TYR2, Sequence: Biotin-(Ahx)-AEEEYFFLFA-amide;2 μM), MOPSO pH 6.5 (50 mM), MgCl₂ (10 mM), MnCl₂ (2 mM), DTT (2.5 mM),BSA (0.01% w/v), Na₃VO₄ (0.1 mM) and ATP (0.001 mM). After about 60 minincubation at rt, the reaction was quenched by addition of EDTA (finalconcentration: 100 mM) and developed by addition of revelation reagents(final approximate concentrations: 30 mM HEPES pH 7.0, 0.06% BSA, 0.006%Tween-20, 0.24 M KF, 80 ng/mL PT66K (europium labeledanti-phosphotyrosine antibody cat #61T66KLB Cisbio, Bedford, Mass.) and3.12 μg/mL SAXL (Phycolink streptavidin-allophycocyanin acceptor, cat#PJ52S, Prozyme, San Leandro, Calif.). The developed reaction wasincubated in the dark either at about 4° C. for about 14 h or for about60 min at rt, then read via a time-resolved fluorescence detector(Rubystar, BMG) using a 337 nm laser for excitation and emissionwavelength of 665 nm. Within the linear range of the assay, the observedsignal at 665 nm is directly related to phosphorylated product and usedto calculate the IC₅₀ values.

In Vitro Jak3 Kinase Activity Measured by Time-Resolved FluorescenceResonance Energy Transfer (trFRET)

Varying concentrations of inhibitor were added to an assay wellcontaining: Jak3 enzyme (aa 811-1103; expressed in SF9 cells as a GSTfusion and purified by glutathione affinity chromatography; 3 nM),peptide substrate (biotin-TYR2, Sequence: Biotin-(Ahx)-AEEEYFFLFA-amide;2 μM), MOPSO pH 6.5 (50 mM), MgCl₂ (10 mM), MnCl₂ (2 mM), DTT (2.5 mM),BSA (0.01% w/v), Na₃VO₄ (0.1 mM) and ATP (0.001 mM). After about 60 minincubation at rt, the reaction was quenched by addition of EDTA (finalconcentration: 100 mM) and developed by addition of revelation reagents(final approximate concentrations: 30 mM HEPES pH 7.0, 0.06% BSA, 0.006%Tween-20, 0.24 M KF, 80 ng/mL PT66K (europium labeledanti-phosphotyrosine antibody cat #61T66KLB Cisbio, Bedford, Mass.) and0.8 μg/mL SAXL (Phycolink streptavidin-allophycocyanin acceptor, cat#PJ52S, Prozyme, San Leandro, Calif.). The developed reaction wasincubated in the dark either at about 4° C. for about 14 h or for about60 min at rt, then read via a time-resolved fluorescence detector(Rubystar, BMG) using a 337 nm laser for excitation and emissionwavelength of 665 nm. Within the linear range of the assay, the observedsignal at 665 nm is directly related to phosphorylated product and usedto calculate the IC₅₀ values.

In Vitro Syk Kinase Activity Measured by Time-Resolved FluorescenceResonance Energy Transfer (trFRET)

0.3 nM Syk catalytic domain (aa356-635, purified in-house at the AbbottBioreseach Center) was mixed with 0.1 μM peptide substrate (biotin-TYR1,Sequence: Biotin-(Ahx)-GAEEEIYAAFFA-COOH) at varying concentrations ofinhibitor in reaction buffer: 50 mM MOPSO pH 6.5, 10 mM MgCl₂, 2 mMMnCl₂, 2.5 mM DTT, 0.01% BSA, 0.1 mM Na₃VO₄ and 0.001 mM ATP. Afterabout 60 min incubation at rt, the reaction was quenched by addition ofEDTA (final concentration: 100 mM) and developed by addition ofrevelation reagents (final approximate concentrations: 30 mM HEPES pH7.0, 0.06% BSA, 0.006% Tween-20, 0.24 M KF, 90 ng/mL PT66K (europiumlabeled anti-phosphotyrosine antibody cat #61T66KLB Cisbio, Bedford,Mass.) and 0.6 μg/mL SAXL (Phycolink streptavidin-allophycocyaninacceptor, cat #PJ52S, Prozyme, San Leandro, Calif.). The developedreaction was incubated in the dark either at about 4° C. for about 14 hor for about 60 min at rt, then read via a time-resolved fluorescencedetector (Rubystar, BMG) using a 337 nm laser for excitation andemission wavelength of 665 nm. Within the linear range of the assay, theobserved signal at 665 nm is directly related to phosphorylated productand used to calculate the IC₅₀ values.

Other In Vitro Kinase Assays Measured by Time-Resolved FluorescenceResonance Energy Transfer (trFRET)

Other kinase assays were performed using a similar protocol. Additionalpurified enzymes Tyk2 (aa 880-1185 with an N-terminal histidine-tag andC-terminal FLAG tag; purified in-house by immobilized metal ion affinitychromatography), RET (aa 711-1072 with an N-terminal histidine-tag;purified by immobilized metal ion affinity chromatography), Syk(aa356-635 with a C-terminal histidine tag; purified by immobilizedmetal ion affinity chromatography), and KDR (aa 792-1354 with anN-terminal histidine-tag; purified in-house by immobilized metal ionaffinity and ion-exchange chromatography) were expressed in SF9 cellsand Aurora 1/B (aa 1-344 with a N-terminal histidine-tag and purified byimmobilized metal ion affinity chromatography) was expressed in E. coli.Other enzymes used are available from commercial sources. Enzymes weremixed with biotinylated substrates at varying concentrations ofinhibitor in different reaction buffers (see Table A). After about 60min incubation at rt, the reaction was quenched by addition of EDTA anddeveloped by addition of revelation reagents (final approximateconcentrations: 30 mM HEPES pH 7.0, 0.06% BSA, 0.006% Tween-20, 0.24 MKF, varying amounts of donor europium labeled antibodies and acceptorstreptavidin labeled allophycocyanin (SAXL)). The developed reactionswere incubated in the dark either at about 4° C. for about 14 h or forabout 60 min at rt, then read in a time-resolved fluorescence detector(Rubystar, BMG Labtech) as described above.

TABLE A Specific conditions (per 40 μL enzyme reaction) for the variousenzymes are detailed below: Enzyme ATP DMSO Reaction Assay Conc.Substrate Conc. Conc. Time Detection Enzyme Construct Substrate Buffer(ng/well) Conc. (mM) (%) (min) condition Jak1 aa 845-1142 Biotin-TYR2MOPSO 5 2 μM 0.001 5 60 8 ng/well PT66K, 0.39 μg/well SAXL Jak2Millipore Biotin-TYR1 MOPSO 2.5 2 μM 0.001 5 60 8 ng/well cat# 14-640PT66K, 0.078 μg/well SAXL Jak3 aa 811-1103 Biotin-TYR2 MOPSO 4.5 2 μM0.001 5 60 8 ng/well PT66K, 0.078 μg/well SAXL Tyk2 aa880-1185Biotin-TYR1 MOPSO 9 2 μM 0.001 5 60 8 ng/well PT66K, 0.078 μg/well SAXLAurora aa1-344 KinEASE MOPS 20 0.5 μM 0.1 5 60 15 ng/well 1/B S2Eu-STK-Ab, 0.34 μg/wel SAXL KDR aa789-1354 Biotin-TYR2 HEPES 10 2 μM 0.15 60 8 ng/well PT66K, 0.078 μg/well SAXL JNK1 Millipore Biotin-ATF2-pepMOPS 10 1 μM 0.01 5 60 2.58 ng/well cat# 14-327 Anti-pATF2-Eu, 0.6μg/well SAXL JNK2 Millipore Biotin-ATF2-pep MOPS 5 0.5 μM 0.01 5 60 2.58ng/well cat# 14-329 Anti-pATF2-Eu, 0.6 μg/well SAXL RET aa711-1072Biotin-poly HEPES 4 10 ng/well 0.01 5 60 8 ng/well GluTyr PT66K, 0.078μg/well SAXL P70 S6 Millipore KinEASE MOPS 0.5 0.25 μM 0.01 5 60 15ng/well Kinase cat # 14-486 S3 Eu-STK-Ab, 0.34 μg/well SAXL PKN2Invitrogen KinEASE MOPS 0.7 0.5 μM 0.001 5 60 15 ng/well cat # PV3879 S3Eu-STK-Ab, 0.34 μg/well SAXL Syk aa356-635 Biotin-TYR1 MOPSO 0.4 0.1 μM0.001 5 60 6.8 ng/well PT66K, 0.045 μg/well SAXL CDK2/Cyclin MilliporeBiotin-MBP MOPS 50 2 μM 0.1 5 60 15 ng/well A cat # 14-448 Anti-pMBP-Eu;0.34 μg/well SAXL

Reaction Buffers:

MOPSO buffer contains: 50 mM MOPSO pH 6.5, 10 mM MgCl₂, 2 mM MnCl₂, 2.5mM DTT, 0.01% BSA, and 0.1 mM Na₃VO₄

HEPES buffer contains: 50 mM HEPES pH 7.1, 2.5 mM DTT, 10 mM MgCl₂, 2 mMMnCl₂, 0.01% BSA, and 0.1 mM Na₃VO₄

MOPS buffer contains: 20 mM MOPS pH 7.2, 10 mM MgCl₂, 5 mM EGTA, 5 mMBeta-phosphoglycerol, 1 mM Na₃VO₄, 0.01% Triton-X-100 and 1 mM DTT

Substrates:

Biotin-ATF2-peptide sequence: Biotin-(Ahx)-AGAGDQTPTPTRFLKRPR-amideBiotin-TYR1-peptide sequence: Biotin-(Ahx)-GAEEEIYAAFFA-COOHBiotin-TYR2-peptide sequence: Biotin-(Ahx)-AEEEYFFLFA-amideBiotin-MBP-peptide sequence:Biotin-(Ahx)-VHFFKNIVTPRTPPPSQGKGAEGQR-amideBiotin-polyGluTyr peptide was purchased from Cisbio (cat #61GT0BLA,Bedford, Mass.)KinEASE S2 and S3 peptides were purchased from Cisbio (cat #62ST0PEB,Bedford, Mass.)

Detection Reagents:

Anti-pATF2-Eu was custom-labeled by Cisbio (Bedford, Mass.)Anti-pMBP-Eu was custom-labeled by Cisbio (Bedford, Mass.)PT66K was purchased from Cisbio (cat #61T66KLB, Bedford, Mass.)SAXL was purchased from Prozyme (cat #PJ25S, San Leandro, Calif.)Human T-Blasts IL-2 pSTAT5 Cellular Assay

Materials:

Phytohemaglutinin T-blasts were prepared from Leukopacks purchased fromBiological Specialty Corporation, Colmar, Pa. 18915, and cryopreservedin 5% DMSO/media prior to assay. For this assay the cells were thawed inassay medium with the following composition: RPMI 1640 medium (Gibco11875093) with 2 mM L-glutamine (Gibco 25030-081), 10 mM HEPES (Gibco15630-080), 100 μg/mL Pen/Strep (Gibco 15140-122), and 10% heatinactivated FBS (Gibco 10438026). Other materials used in the assay:DMSO (Sigma D2650), 96-well dilution plates (polypropylene) (Corning3365), 96-well assay plates (white, ½ area, 96 well) (Corning 3642),D-PBS (Gibco 14040133), IL-2 (R&D 202-IL-10 (10 μg)), Alphascreen pSTAT5kit (Perkin Elmer TGRS5S10K) and Alphascreen protein A kit (Perkin Elmer6760617M)

Methods:

T-Blasts were thawed and cultured for about 24 h without IL-2 prior toassay. Test compounds or controls are dissolved and serially diluted in100% DMSO. DMSO stocks are subsequently diluted 1:50 in cell culturemedia to create the 4× compound stocks (containing 2% DMSO). Using aCorning white 96 well, ½ area plate, cells are plated at 2×10⁵/10μl/well in 10 μL media followed by addition of 5 μL of 4× test compoundin duplicate. Cells are incubated with compound for about 0.5 h at about37° C. Next, 5 μL of IL-2 stock is added at 20 ng/mL finalconcentration. IL-2 is stored as a 4 μg/mL stock solution, as specifiedby the manufacturer, at about 20° C. in aliquots and diluted 1:50 withassay media (to 80 ng/mL) just prior to use. The contents of the wellsare mixed by carefully tapping sides of plate(s) several times followedby incubation at about 37° C. for about 15 min. The assay is terminatedby adding 5 μL of 5× AlphaScreen lysis buffer and shaking on an orbitalshaker for about 10 min at rt. Alphascreen acceptor bead mix isreconstituted following Perkin Elmer's protocol. 30 μL/well ofreconstituted Alphascreen acceptor bead mix was added, covered with foilthen shaken on orbital shaker for about 2 min on high then about 2 h onlow. Donor bead mix is reconstituted following Perkin Elmer'sAlphaScreen protocol; 12 μL/well are added, covered with foil thenshaken for about 2 min on high, and about 2 h on low. Plates are read onan EnVision reader following Perkin Elmer's AlphaScreen protocolinstructions.

TF-1 IL-6 pSTAT3 Cellular Assay

Materials:

TF-1 cells (ATCC #CRL-2003). Culture medium: DMEM medium (Gibco11960-044) with 2 mM L-glutamine (Gibco 25030-081), 10 mM HEPES (Gibco15630-080), 100 μg/mL Pen/Strep (Gibco 15140-122), 1.5 g/L sodiumbicarbonate (Gibco 25080-094), 1 mM sodium pyruvate (Gibco 11360-070),10% heat inactivated FBS (Gibco 10437-028), and 2 ng/mL GM-CSF (R&D215-GM-010). Other materials used in this assay: DMSO (Sigma D2650),96-well dilution plates (polypropylene) (Corning 3365), 96-well assayplates (white, ½ area, 96 well) (Corning 3642), D-PBS (Gibco 14040133),IL-6 (R&D 206-IL/CF-050 (50 μg)), Alphascreen pSTAT3 kit (Perkin ElmerTGRS3S10K) and Alphascreen protein A kit (Perkin Elmer 6760617M).

Methods:

Prior to the assay, cells are cultured for about 18 h in the culturemedium without GM-CSF. Test compounds or controls are dissolved andserially diluted in 100% DMSO. DMSO stocks are subsequently diluted 1:50in cell culture media to create the 4× compound stocks (containing 2%DMSO). Using a Corning white 96 well, ½ area plate, cells are plated at2×10⁷/10 μL/well in 10 μL media followed by addition of 5 μL of the 4×test compound stock in duplicate. Cells are incubated with compound forabout 0.5 h at about 37° C. followed by addition of 5 μL of 400 ng/mLIL-6. IL-6 is stored in 10 μg/mL aliquots using endotoxin free D-PBS(0.1% BSA) at about 20° C. Prior to assay IL-6 is diluted to 400 ng/mLin culture media and applied (5 μL/well) to all wells, except tonegative control wells where 5 μL/well of media is added. The contentsof the wells are mixed carefully by tapping the side of the plateseveral times. Plates are incubated at about 37° C. for about 30 min.Cells are lysed by adding 5 μL of 5× AlphaScreen cell lysis buffer toall wells, shaken for about 10 min at rt then assayed. Alternatively,assay plates may be frozen at about −80° C. and thawed later at rt.Using the pSTAT3 SureFire Assay kit (Perkin Elmer #TGRS3S10K) acceptorbead mix is reconstituted following Perkin Elmer's AlphaScreen protocolinstructions. 30 μL are added per well then the plate is covered withfoil and shaken on an orbital shaker for about 2 min on high, then about2 h on low at rt. Donor bead mix is reconstituted following PerkinElmer's AlphaScreen protocol instructions. 12 μL are added per well,then covered with foil and shaken on orbital shaker for about 2 min onhigh, then about 2 h on low at about 37° C. Plates are read on anEnVision reader following Perkin Elmer's AlphaScreen protocolinstructions at rt.

UT7/EPO pSTAT5 Cellular Assay

Materials:

UT7/EPO cells are passaged with erythropoietin (EPO), split twice perweek and fresh culture medium is thawed and added at time of split.Culture Medium: DMEM medium (Gibco 11960-044) with 2 mM L-glutamine(Gibco 25030-081), 10 mM HEPES (Gibco 15630-080), 100 U/mL Pen/Strep(Gibco 15140-122), 10% heat inactivated FBS (Gibco 10437-028), EPO (5μL/mL=7.1 μL of a 7 μg/mL stock per mL of medium). Assay media: DMEM, 2mM L-glutamine, 5% FBS, 10 mM HEPES. Other materials used in the assay:DMSO (Sigma D2650), 96-well dilution plates (polypropylene) (Corning3365), 96-well assay plates (white, ½ area, 96 well) (Corning 3642),D-PBS (Gibco 14040133), IL-2 (R&D 202-IL-10 (10 μg)), Alphascreen pSTAT5kit (Perkin Elmer TGRS5S10K) and Alphascreen protein A kit (Perkin Elmer6760617M).

Methods:

Culture cells for about 16 h without EPO prior to running assay. Testcompounds or controls are dissolved and serially diluted in 100% DMSO.DMSO stocks are subsequently diluted 1:50 in cell culture media tocreate the 4× compound stocks (containing 2% DMSO). Using a Corningwhite 96 well, ½ area plate, cells are plated at 2×10⁵/10 μL/well in 10μL media followed by addition of 5 μL of 4× test compound stock induplicate. Cells are incubated with compound for about 0.5 h at about37° C. After incubation, 5 μL of EPO is added to afford a finalconcentration of 1 nM EPO. The contents of the wells are mixed bycarefully tapping sides of the plate several times followed byincubation at about 37° C. for about 20 min. 5 μL of 5× AlphaScreenlysis buffer are added followed by shaking on an orbital shaker forabout 10 min at rt. 30 μL/well of acceptor beads are added afterreconstitution following Perkin Elmer's AlphaScreen protocol, coveredwith foil and shaken on orbital shaker for about 2 min on high, thenabout 2 h on low. Donor beads are reconstituted following Perkin Elmer'sAlphaScreen protocol instructions followed by addition of 12 μL/well,covered with foil and shaken on an orbital shaker for about 2 min onhigh, about 2 h on low. Plates are read on an EnVision reader followingPerkin Elmer's AlphaScreen protocol instructions.

Antigen-Induced Degranulation of RBL-2H3 Cells:

RBL-2H3 cells are maintained in T75 flasks at about 37° C. and 5% CO₂,and passaged every 3-4 days. To harvest cells, 20 mL of PBS is used torinse the flask once, and then 3 mL of Trypsin-EDTA is added andincubated at about 37° C. for about 2 min. Cells are transferred to atube with 20 mL medium, spun down at 1000 RPM at rt for about 5 min andresuspended at 1×10⁶ cells/mL. Cells are sensitized by addingDNP-specific mouse IgE to a final concentration of 0.1 μg/mL. 50 μL ofcells are added to each well of a 96 well flat bottom plate (50×10³cells/well) and incubated overnight at about 37° C. in 5% CO₂. The nextday, compounds are prepared in 100% DMSO at 10 mM. Each compound is thenserially diluted 1:4 six times in 100% DMSO. Each compound dilution isthen diluted 1:20 and then 1:25, both dilutions in Tyrode's buffer.Media is aspirated from the cell plates and the cells are rinsed twicewith 100 μL of Tyrode's buffer (prewarmed to about 37° C.). 50 μL ofcompounds diluted in Tyrode's buffer are added to each well and theplates are incubated for about 15 min at about 37° C. in 5% CO₂. 50 μLof 0.2 μg/mL DNP-HSA in Tyrode's buffer is then added to each well andthe plates are incubated for about 30 min at about 37° C. in 5% CO₂. Thefinal concentration of the various components in the incubation mix are0.002-10 μM compounds, 0.1% DMSO, and 0.1 μg/mL DNP-HSA. As one control,0.2% DMSO (no compound) in Tyrode's buffer is added to a set of wells todetermine maximum stimulated release. As a second control, Tyrode'sbuffer without DNP-HSA is added to a set of wells with containing 0.2%DMSO without compounds to determine unstimulated release. Each condition(compounds and controls) is set up in triplicate wells. At the end ofthe min incubation, 50 μL of supernate is transferred to a new 96 wellplate. The remaining supernate in the cell plates is aspirated andreplaced with 50 μL of 0.1% Triton X-100 in Tyrode's buffer to lyse thecells. 50 μL of freshly prepared 1.8 mM 4-NitrophenylN-acetyl-β-D-glucosaminide (pNAG) is then added to each well ofsupernate and cell lysate and the plates are incubated for about 60 minat about 37° C. in 5% CO₂. 100 μL of 7.5 mg/mL sodium bicarbonate isadded to each well to stop the reaction. The plates are then read at 405nm on a Molecular Devices SpectraMax 250 plate reader.

Calculation of Results

1) The plate background OD₄₀₅ obtained from wells containing Tyrode'sbuffer and pNAG (no supernate or lysate) is subtracted from the OD₄₀₅reading for each well containing supernate or lysate.2) The release for each well is expressed as the percentage of the totalrelease for that well, where the total release is twice the release inthe supernate plus the release in the cell lysate. This calculationcorrects for variable cell number in each well.3) The maximum response is the mean response of wells containing DNP-HSAbut no compound.4) The minimum response is the mean response of wells containing noDNP-HSA and no compound.5) The response in each compound well is calculated as a percentage ofthe maximum response (expressed as % control) where the maximum responseis 100% and the minimum response is 0%.6) A dose response curve is generated for each compound and the IC₅₀ ofthe curve is calculated using Prism GraphPad software and nonlinearleast squares regression analysis.

Acute In Vivo Measurement of JAK Inhibition by Compounds is MeasuredUsing the: Concanavalin A (Con A)-Induced Cytokine Production in LewisRats

The test compound is formulated in an inert vehicle (for example but notlimited to 0.5% hydroxypropylmethyl cellulose (Sigma, cat #H3785)/0.02%Tween 80 (Sigma, cat #4780) in water) at the desired concentration toachieve doses in the range of 0.01-100 mg/kg. Six-week-old male Lewisrats (125 g-150 g) (Charles River Laboratories) are dosed with thecompound orally, at time zero (0 min). After about 30 min the rats areinjected intravenously (i.v.) with 10 mg/kg Concanavalin A (Con A,AmershamBioscience, cat #17-0450-01) dissolved in PBS (Invitrogen, cat#14190). About 4 h later, the rats are cardiac bled and their plasma isanalyzed for levels of IL-2 (ELISA kit: R&D Systems cat #R2000) andIFN-γ (ELISA kit: R&D Systems cat #RIF00).

Acute In Vivo Measurement of Fcγ Receptor Signaling Inhibition of theCompounds is Measured Using the: Reverse Passive Arthus Model

On day 0, OVA was made up at a concentration of 17.5 mg/mL, in PBS byrocking gently until a solution was formed. 2% Evans Blue solution(Sigma Aldrich, cat #E2129) was then added to double the volume for afinal concentration of 8.75 mg/mL of OVA and 1% Evans Blue dye. Anti-OVAantibody (Abazyme), stock concentration 10 mg/mL, was thawed and a 400μg/100 μL solution was made with PBS. Compounds were made up by addingthe vehicle, 0.5% HPMC with 0.02% Tween80, and vortexing for about 15seconds followed by homogenizing for a minimum of about 2 min at 28,000rpm until there was a fine particulate suspension with no clumps ofcompound. Rats were weighed and dosed with compound at a pre-determinedt-max based on pharmacokinetic studies. Animals were then placed undergeneral anesthesia with a 5% isoflourane and oxygen mixture and shaved.Using a ½ mL insulin syringe two sites were injected i.d., 1 site with100 μL of 400 μg/100 μL of anti-OVA antibody, and 1 site with 100 μL ofsterile PBS. Each site was then circled with permanent marker forexplant later. Right after i.d. injections animals were injected with200 μL of the OVA (10 mg/kg)/Evans Blue mixture i.v., using a ½ mLinsulin syringe. About four hours post injection animals wereeuthanized, bled via cardiac puncture and blood was collected using aplasma separating tube. Blood samples were stored on ice untilcentrifugation (within about 2 h of collection). Each injection site wasremoved with a disposable biopsy punch (Acuderm Acu-Punch Disposable 12mm), cut into four pieces and placed in a pre-labeled 2 mL eppendorftube. One mL of DMF was added to each biopsy tube and placed in a heatblock for about 24 h at about 50° C. About 24 h after incubation 100 μLof each sample was added to a 96 well flat bottom plate. The sampleswere read at 620 nm on a plate reader using the Softmax software inorder to measure the levels of Evan's Blue dye. Background was removedby subtracting the OD from the PBS injected site from the OD of theanti-OVA injected site for each individual animal. Plasma samples werespun down in a microcentrifuge for about 5 min at 16.1 rcf. 200 μL ofplasma was placed in a 1.7 mL eppendorf tube for drug level measurementand tubes were stored at −80° C. until evaluation.

Chronic In Vivo Effects of the Compounds on Anc Arthritis Disease Modelis Measured Using the: Adjuvant Induced Arthritis (AIA) in a Lewis Rat

Female Lewis rats, (6 weeks of age, 125 g-150 g in weight from CharlesRiver Laboratories) are immunized intradermally (i.d.) in the righthind-footpad with 100 μL of a suspension of mineral oil (Sigma, cat#M5905) and containing 200 μg M. tuberculosis, H37RA (Difco, cat tt231141). The inflammation appears in the contra-lateral (left) hind pawseven days after the initial immunization. Seven days post immunization,the compound is formulated in an inert vehicle (for example but notlimited to 0.5% hydroxypropylmethyl cellulose (Sigma, cat#1-13785)/0.02% Tween 80 (Sigma, cat #4780) in water) and dosed orallyonce or twice a day for at least 10 days. Baseline paw volume is takenon day 0 using a water displacement pleythsmograph (Vgo Basile NorthAmerica Inc. PA 19473, Model tt 7140). Rats are lightly anesthetizedwith an inhalant anesthetic (isoflurane) and the contra-lateral (left)hind paw is dipped into the plethysmograph and the paw volume isrecorded. The rats are scored every other day up to day 17 afterimmunization. On day 17 after immunization, all rats are exsanguinatedby cardiac puncture under isoflurane anesthesia, and the left hind pawis collected to assess the impact on bone erosion using micro-CT scans(SCANCO Medical, Southeastern, Pa., Model tt μCT 40) at a voxel size of18 nm, a threshold of 400, sigma-gauss 0.8, support-gauss 1.0. Bonevolume and density is determined for a 360 nm (200 slice) verticalsection encompassing the tarsal section of the paw. The 360 nm sectionis analyzed from the base of the metatarsals to the top of the tibia,with the lower reference point fixed at the tibiotalar junction. Drugexposure is determined in the plasma using LC/MS. or the:

Collagen Induced Arthritis (CIA) in a Lewis Rat

On day −1 Collagen Type II (CII), soluble from bovine nasal septum(Elastin Products, Cat #CN276) was weighed out for a dose of 600 μg/rat,0.01M acetic acid (150 μL HOAc USP grade. J. T. Baker, order#9522-03,and 250 mL Milli Q Water) was added for a concentration of 4 mg/mL. Thevial was covered with aluminum foil and placed on a rocker at about 4°C. overnight. On day 0 collagen stock solution was diluted 1:1 withIncomplete Freunds adjuvant (IFA) (Difco labs, cat #263910) using aglass Hamilton luer lock syringe (SGE Syringe Perfection VWR cat#007230), final concentration 2 mg/mL. Female Lewis rats (Charles RiverLaboratories) acclimated for 7 days at the time of immunization weighingapproximately 150 g were anesthetized in an anesthesia chamber usingisoflurane (5%) and oxygen. Once the rats were completely anesthetized,they were transferred to a nose cone to maintain anesthesia during theinjections. Rats were shaved at the base of the tail, 300 μL of collagenwas injected i.d. on the rump of the rat, n=9 per group. 100 μL at threesites with a 500 μL leur lock syringe and a 27 g needle. IFA controlrats are injected in the same manner (n=6). The IFA is a 1:1 emulsionwith the 0.01M acetic acid. Boost was done on day 6 of the study.Shaving was not done on this day and injections were done in the samemanner as the immunization. The inflammation appears in both hind paws10 days after the initial immunization. 10 days post immunization, thecompound was formulated in an inert vehicle (for example but not limitedto 0.5% hydroxypropylmethyl cellulose (Sigma, cat #H3785)/0.02% Tween 80(Sigma, cat #4780) in water) and dosed orally once or twice a day for atleast 9 days. Baseline paw volume was taken on day 7 using a waterdisplacement pleythsmograph (Vgo Basile North America Inc. PA 19473,Model #7140). Rats were lightly anesthetized with an inhalant anesthetic(isoflurane) and both hind paws were dipped into the plethysmograph andthe paw volume was recorded. The rats were scored 2 to 3 times a week upto day 18 after immunization. On day 18 after immunization, all ratswere exsanguinated by cardiac puncture under isoflurane anesthesia, andthe hind paws were collected to assess the impact on bone erosion usingmicro-CT scans (SCANCO Medical, Southeastern, Pa., Model # ACT 40) at avoxel size of 18 μm, a threshold of 400, sigma-gauss 0.8, support-gauss1.0. Bone volume and density was determined for a 360 μm (200 slice)vertical section encompassing the tarsal section of the paw. The 360 μmsection was analyzed from the base of the metatarsals to the top of thetibia, with the lower reference point fixed at the tibiotalar junction.Drug exposure was determined from plasma using LC/MS.

Chronic In Vivo Effects of the Compounds on an Asthma Disease Model isMeasured Using the: OVA Induced Rat Asthma Model

Female Brown Norway rats (7-9 weeks of age) were sensitized on day 0 and7 with 40 μg ovalbumin (OVA) (Sigma-Aldrich, St. Louis, Mo.) in a 20mg/ml solution of Alum Imject (Pierce, Rockford, Ill.). The rats weresubsequently challenged intratracheally on day 19 and 20 with 1.5 μg OVAin 50 μL PBS. Dosing of inhibitor began on day 18 and continues throughday 22. On day 22, 48 h after the second challenge, rats were subjectedto an anesthetized and restrained pulmonary function test. Airwayhyperresponsiveness (AHR) was assessed using whole body plethysmography.Briefly, a surgical plane of anesthesia was induced with anintraperitoneal injection of 60 mg/kg ketamine and 5 mg/kg xylazine(Henry Schein, Inc., Melville, N.Y.). A tracheal cannula was surgicallyinserted between the 3rd and 4th tracheal rings. Spontaneous breathingwas prevented by jugular vein injection of 0.12 mg/kg pancuroniumbromide (Sigma-Aldrich, St Louis, Mo.). Animals were placed in a wholebody plethysmograph (Buxco Electronics, Inc., Wilmington, N.C.) andmechanically ventilated with 0.2 mL room air at 150 breaths per minutewith a volume controlled ventilator (Harvard Apparatus, Framingham,Mass.). Pressure in the lung and flow within the plethysmograph weremeasured using transducers and lung resistance was calculated aspressure/flow using Biosystem Xa software (Buxco Electronics). Airwayresistance was measured at baseline and following challenge with 3, 10,and 30 mg/mL methacholine (Sigma Aldrich, St. Louis, Mo.) delivered withan inline ultrasonic nebulizer. Upon completion of pulmonary functiontesting, the lungs were lavaged 3 times with 1 mL sterile PBS. Thevolume from the first wash was centrifuged at 2000 rpm for 5 min, andthe supernatant is stored for subsequent analysis. The volume of washes2 through 3 are added to the pellet derived from the first wash andsubsequently processed for evaluation of cellular infiltrate by flowcytometry. Plasma was collected from blood drawn from the vena cava andwas used for evaluation of drug concentrations.

The teachings of all references, including journal articles, patents andpublished patent applications, are incorporated herein by reference intheir entirety.

The following examples are for illustrative purposes and are not to beconstrued as limiting the scope of the present invention.

General Synthetic Schemes

Compounds of the invention may be prepared using the synthetictransformations illustrated in Schemes I-XXVIII. Starting materials arecommercially available, may be prepared by the procedures describedherein, by literature procedures, or by procedures that would be wellknown to one skilled in the art of organic chemistry. Methods forpreparing pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine compounds of theinvention are illustrated in Scheme I. In Scheme I, step a, commerciallyavailable 3,5-dibromopyrazin-2-amine 1 is reacted with a(trimethylsilyl)acetylene via a Sonogashira cross coupling using methodsknown to one skilled in the art (for example Example #1 orWO2006058120A1) to give alkyne 2. Alkyne 2 can be cyclized (Scheme I,step b) to provide protected pyrrolo[2,3-b]pyrazine 3 using methodsknown to one skilled in the art (for example Example #1 orWO2006058120A1). In Scheme I, step c, a substituted hydrazine isintroduced by reaction with pyrrolopyrazines 3 under Buchwald-Hartwigamination conditions (for example Example #1 or Advanced Synthesis &Catalysis 2004, 346, 1599-1626) to give pyrrolopyrazines 4. If R″ issuch that pyrrolopyrazines 4 contain a hydrazide (R″═—C(O)R′″), thematerial may be directly cyclized to pyrrolotriazolopyrazines 7 (SchemeI, step h) using conditions such as those described in GeneralProcedures B or ZZZZ or by methods known to one skilled in the art (forexample Bioorganic & Medicinal Chemistry Letters 2007, 17(12), 3373-3377or Journal of Medicinal Chemistry 1990, 33(9), 2326-2334). If R″ is aprotecting group, deprotection of compounds 4 (Scheme I, step d) toyield hydrazinylpyrrolopyrazines 5 can be performed using conditionssuch as those described in General Procedures E, E.1, F, F.1, Y or BB;or Greene, T. W. and Wuts, P. G. M. “Protective Groups in OrganicSynthesis, 3^(rd) Edition”, 1999, Wiley-Interscience. For example, aprotecting group such as a t-butoxycarbonyl (Boc) group can be removedwith acid using conditions such as those described in Example #1,General Procedures E and E.1, or by methods known to one skilled in theart (for example, the books from Larock, R. C. “Comprehensive OrganicTransformations: A Guide to Functional Group Preparations, 2^(nd)edition”, 1999, Wiley-VCH or Greene, T. W. and Wuts, P. G. M. referencedabove). The formation of hydrazides 6 from hydrazinylpyrrolopyrazines 5(Scheme I, step e) may be accomplished by a variety of methods known toone skilled in the art including in situ conditions such as thosedescribed in Example #1, General Procedure A, or standard peptidecoupling methods such as those found in Larock, R. C. referenced above.The hydrazides 6 may be cyclized to pyrrolotriazolopyrazines 7 usingconditions such as those described in Example #1, General Procedures B,OO, OO.1, or ZZZZ, or by methods known to one skilled in the art (forexample, Bioorganic & Medicinal Chemistry Letters 2007, 17(12),3373-3377 or Journal of Medicinal Chemistry 1990, 33(9), 2326-34).Further functionalization of hydrazides 6 or pyrrolotriazolopyrazines 7can be performed, if desired, using reactions known to one skilled inthe art (for example, Larock, R. C. referenced above). For example,formation of amides, ureas, sulfonamides, aryl amines, heteroarylamines, sulfonyl ureas, substituted amines, squaramides, or guanidinescan be prepared from pyrrolotriazolopyrazines 7 containing a primary orsecondary amine (for example General Procedures G, H, I, J, J.1, XXX,EEEE, K, K.1, L, DD, QQ, RR, YY, ZZ followed by AAA, CCC, YYY, X, X.1,TTTT, or EEEEE). Also, deprotection of hydrazides 6 orpyrrolotriazolopyrazines 7 containing a protected primary or secondaryamine can be performed using conditions such as those described inGreene, T. W. and Wuts, P. G. M. referenced above or in GeneralProcedures E, E.1, F, F.1, or BB. For example, for R′″ containing aprotecting group such as a benzyloxycarbonyl (Cbz) group, the protectinggroup can be removed to yield the unprotected amine (for example GeneralProcedures F, F.1, and DDDDD) and the deprotected compounds 7 may thenbe reacted further as described above. In some cases, additionalreactions may also occur without isolation of initialpyrrolotriazolopyrazines 7 as seen in General Procedure C.Alternatively, hydrazinylpyrrolopyrazines 5 may be directly cyclized topyrrolotriazolopyrazines 7 (Scheme I, step i) using conditions such asthose described in General Procedure BBBBB. Removal of the sulfonamideprotecting group of pyrrolotriazolopyrazines 7 may be accomplished usingconditions such as those described in Example #1, General Procedures D,XXX, AAAA, BBBB, or CCCC or by methods known to one skilled in the art(for example, the books from Larock, R. C. or Greene, T. W. and Wuts, P.G. M. referenced above) to give pyrrolotriazolopyrazines 8 (Scheme I,step g). Further functionalization of the R′″ group inpyrrolotriazolopyrazines 8 can be performed, if desired, using reactionsknown to one skilled in the art (for example, Larock, R. C. referencedabove). For example, amides, ureas, sulfonamides, aryl amines,heteroaryl amines, sulfonyl ureas, substituted amines, squaramides, orguanidines can be prepared from pyrrolotriazolopyrazines 8 with an R′″containing a primary or secondary amine (for example Examples #8-9 orGeneral Procedures G, H, I, J, J.1, XXX, EEEE, K, K.1, L, DD, QQ, RR,YY, ZZ followed by AAA, CCC, YYY, X, X.1, TTTT, or EEEEE). Also,deprotection of the R′″ group in pyrrolotriazolopyrazines 8 to yield anunprotected compound can be performed using conditions such as thosedescribed in Greene, T. W. and Wuts, P. G. M. referenced above or inGeneral Procedures E, E.1, F, F.1, Y, or BB. For example, a protectinggroup such as a benzyloxycarbonyl (Cbz) group can be removed from aprotected amine to yield the unprotected amine (for example GeneralProcedures F, F.1, and DDDDD) and the deprotected compounds 8 may thenbe reacted further as described above.

Methods for preparing imidazo[1,2-a]pyrrolo[2,3-e]pyrazines compounds ofthe invention are illustrated in Scheme II. In step a, Pd-mediatedcarbonylation of pyrrolopyrazines 3 gives esters 9 using methods knownto one skilled in the art such as those described in Example #3; U.S.Pat. Appl. Publ., US 2007293509; or U.S. Pat. Appl. Publ., US2008248537. Hydrolysis of esters 9 gives acids 10 (Scheme II, step b)using well known conditions such as those described in Example #3 orGeneral Procedure Z. A Curtius rearrangement is used to preparecarbamates 11 as shown in Scheme II, step c using conditions such asthose described in Example #3 or referenced in Li, J. J. “NameReactions. A Collection of Detailed Reaction Mechanisms, 2^(nd)edition”, 2003, Springer: New York. Alkylation ofpyrrolopyrazin-2-ylcarbamates 11 with appropriately substituted2-halomethyl ketones (which may be prepared via procedures such as thosedescribed in General Procedures R and LLLL; Tetrahedron Letters, 1992,(33), 309-312) by methods known to one skilled in the art (for exampleGeneral Procedures S or S.1; Tetrahedron Letters, 2006, 47(34),6113-6115; or Journal of Medicinal Chemistry, 2005, 48(14), 4535-4546)yields pyrrolopyrazines 12 (Scheme II, step d). The deprotection ofpyrrolopyrazines 12 to pyrrolopyrazines 13 (Scheme II, step e) isaccomplished using conditions such as those described in GeneralProcedures E and E.1, or in Greene, T. W. and Wuts, P. G. M. referencedabove. As shown in Scheme II, step f, cyclization of pyrrolopyrazines 13to imidazopyrrolopyrazines 14 can be accomplished by methods known toone skilled in the art (for example, General Procedures T or MUCK;Example #3, European Journal of Medicinal Chemistry, 2001, 36(3),255-264; or Bioorganic and Medicinal Chemistry Letters, 2007, 17(5),1233-1237). Further functionalization of the R′″ group inimidazopyrrolopyrazines 14 can be performed, if desired, using reactionsknown to one skilled in the art (for example, Larock, R. C. referencedabove). For example, amides, ureas, sulfonamides, aryl amines,heteroaryl amines, sulfonyl ureas, substituted amines, squaramides, orguanidines can be prepared from imidazopyrrolopyrazines 14 with an R′″group containing a primary or secondary amine (for example, Example #3,Example #7, or General Procedures G, H, I, J, J.1, XXX, EEEE, K, K.1, L,DD, QQ, RR, YY, ZZ followed by AAA, CCC, YYY, X, X.1, TTTT, or EEEEE).Also, deprotection of the R′″ group in imidazopyrrolopyrazines 14 toyield deprotected compounds 14 can be performed using conditions such asthose described in Greene, T. W. and Wuts, P. G. M. referenced above orin General Procedures E, E.1, F, F.1, Y, or BB and the deprotectedcompounds 14 may then be reacted further as described above. Removal ofthe sulfonamide protecting group of imidazopyrrolopyrazines 14 may beaccomplished using conditions such as those described in Example #3,General Procedures D, XXX, AAAA, BBBB, or CCCC or by methods known toone skilled in the art (for example, the books from Larock, R. C. orGreene, T. W. and Wuts, P. G. M. referenced above) to giveimidazopyrrolopyrazines 15 (Scheme II, step g).

Methods for preparing imidazo[1,5-a]pyrrolo[2,3-e]pyrazines compounds ofthe invention are illustrated in Scheme III. In step a, Pd-mediatedcyanation of bromides 3 gives the corresponding nitriles 16 (for exampleExample #5 or Tetrahedron Letters 1999, 40(47), 8193-8195). Subsequentreduction of nitriles 16 gives amines 17 (Scheme III, step b) usingmethods known to one skilled in the art (for example Example #5 orJournal of Medicinal Chemistry 2003, 46(4), 461-473). The coupling ofamines 17 with acids provides amides 18 (Scheme III, step c) using wellknown conditions such as those given in Example #5 or General ProcedureH. As shown in Scheme III, step d, the cyclization of amides 18 can beaccomplished by conversion to the thioamide followed by treatment withan activating agent (such as a mercury salt, a silver salt or a coppersalt) providing the imidazo[1,5-a]pyrrolo[2,3-e]pyrazines 19 (forexample Example #5 or General Procedure Q). Alternatively, if R′″contains a nitrogen such that the compounds 18 are ureas instead ofamides, then cyclization to imidazo[1,5-a]pyrrolo[2,3-e]pyrazines 19 maybe accomplished using POCl₃ as described in General Procedure OO orOO.1. Deprotection of the sulfonamide of compounds 19 to yieldimidazo[1,5-a]pyrrolo[2,3-e]pyrazines 20 (Scheme III, step e) can beperformed using conditions such as those described in Greene, T. W. andWuts, P. G. M. “Protective Groups in Organic Synthesis, 3^(rd) Edition”,1999, Wiley-Interscience, General Procedures D, XXX, AAAA, BBBB, orCCCC, or Example #5. Further functionalization of the R′″ group inimidazo[1,5-a]pyrrolo[2,3-e]pyrazines 19 orimidazo[1,5-a]pyrrolo[2,3-e]pyrazines 20 can be performed, if desired,using reactions known to one skilled in the art (for example, Larock, R.C. referenced above). For example, formation of amides, ureas,sulfonamides, aryl amines, heteroaryl amines, sulfonyl ureas,substituted amines, squaramides, or guanidines can be prepared fromcompounds 19 or 20 with an R′″ group containing a primary or secondaryamine (for example, Example #6, or General Procedures G, H, I, J, J.1,XXX, EEEE, K, K.1, L, DD, QQ, RR, YY, ZZ followed by AAA, CCC, YYY, X,X.1, TTTT, or EEEEE). Also, deprotection of the R′″ group in compounds19 or 20 to yield an unprotected compound can be performed usingconditions such as those described in Greene, T. W. and Wuts, P. G. M.referenced above or in General Procedures E, E.1, F or F.1 and thedeprotected compounds may then be reacted further as described above.

Methods for preparing 4-substituted piperidine-3-carboxylic acidcompounds of the invention are illustrated in Scheme IV. In step a,4-substituted nicotinic acids 21 may be fully saturated using methodsthat are known to one skilled in the art (for example, General ProcedureO or Bioorganic and Medicinal Chemistry Letters 2004, 14(17),4453-4459). The resulting piperidines 22 may be protected with asuitable amine protecting group (Scheme IV, step b) such as thosedescribed in Greene, T. W. and Wuts, P. G. M. “Protective Groups inOrganic Synthesis, 3rd Edition”, 1999, Wiley-Interscience; Larock, R. C.“Comprehensive Organic Transformations: A Guide to Functional GroupPreparations, 2^(nd) edition”, 1999, Wiley-VCH or General Procedures M,M.1, or N to give protected piperidines 23.

Methods for preparing amino-substituted cyclopentyl carboxylic acids 32for use in the preparation of compounds of the invention are illustratedin Scheme V. In step a, β-ketoesters 24 may be condensed with an alkyl4-chloroacetoacetate 25 to give cyclic β-ketoester enolate salts 26 (forexample, General Procedure U). Decarboxylation of compounds 26 to giveα,β-unsaturated ketones 27 (Scheme V, step b) is accomplished bystandard methods known to one skilled in the art (for example, GeneralProcedure V). As shown in step c, hydrogenation of α,β-unsaturatedketones 27 provides the saturated ketones 28 (for example, GeneralProcedures W or W.1). Reductive amination of ketones 28 withdibenzylamine yields compounds 29 (Scheme V, step d) using conditionssuch as those described in General Procedures X or X.1. Thedebenzylation of compounds 29 may be accomplished via hydrogenation asdescribed in General Procedure Y to give amines 30 (Scheme V, step e).Alternate conditions may be used to access amines 30 from ketones 28,for example, as described in Larock, R. C. “Comprehensive OrganicTransformations: A Guide to Functional Group Preparations, 2^(nd)edition”, 1999, Wiley-VCH (Scheme V, step h). Amines 30 may undergofurther functionalization using reactions known to one skilled in theart (for example, Larock, R. C. referenced above). For example, amides,ureas, sulfonamides, aryl amines, heteroaryl amines, sulfonyl ureas,substituted amines, squaramides, or guanidines can be prepared fromamines 30 (for example, General Procedures G, H, I, J, J.1, XXX, EEEE,K, K.1, L, DD, QQ, RR, YY, ZZ followed by AAA, CCC, YYY, X, X.1, TTTT,or EEEEE) to give compounds 31 (Scheme V, step f). The ester ofcompounds 31 may be hydrolyzed under aqueous base or acid conditions togive the desired carboxylic acids 32 (Scheme V, step g) using conditionssuch as those described in General Procedures Z or TT or Larock, R. C.referenced above). Alternatively, the ester of compounds 29 may behydrolyzed to give intermediate carboxylic acids 32′ as shown in SchemeV, step i, using aqueous base or acid conditions (for example,Preparation #TT.1).

Methods for preparing ether-substituted1-cyclopentyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine compoundsof the invention are illustrated in Scheme VI. As shown in step a,reduction of α,β-unsaturated ketones 27 with concomitant reduction ofthe ketone provides the saturated alcohols 33 (for example, the chiralreduction conditions described in Example #4). Alternate conditions maybe used to access alcohols 33 from ketones 28 via reduction (Scheme VI,step b) as described in General Procedure P or in Larock, R. C.“Comprehensive Organic Transformations: A Guide to Functional GroupPreparations, 2^(nd) edition”, 1999, Wiley-VCH. The alcohols 33 may bereacted to give ethers 34 (Scheme VI, step c) using conditions such asthose described in General Procedure EE (which may require first makingthe 2,2,2-trichloroimidate as described in General Procedure UU), II,JJ, or VV followed by General Procedure FFF or by methods known to oneskilled in the art (for example, Tet. Lett. 1983, 24(48), 5363 orGreene, T. W. and Wuts, P. G. M. “Protective Groups in OrganicSynthesis, 3^(rd) Edition”, 1999, Wiley-Interscience). The ester ofcompounds 34 may be hydrolyzed under aqueous base or acid conditions togive the desired carboxylic acids 35 (Scheme VI, step d), usingconditions such as those described in General Procedure Z or TT orLarock, R. C. referenced above. The formation of hydrazides 36 fromhydrazinylpyrrolopyrazines 5 and carboxylic acids 35 (Scheme VI, step e)may be accomplished by a variety of methods known to one skilled in theart such as those described in General Procedure A or standard peptidecoupling methods such as those found in Larock, R. C. referenced above.The hydrazides 36 may be cyclized to pyrrolotriazolopyrazines 37 (SchemeVI, step f) using conditions such as those described in GeneralProcedures B or ZZZZ or by methods known to one skilled in the art (forexample, Bioorganic & Medicinal Chemistry Letters 2007, 17(12),3373-3377 or Journal of Medicinal Chemistry 1990, 33(9), 2326-2334).Removal of the sulfonamide protecting group of pyrrolotriazolopyrazines37 may be accomplished using conditions such as those described inGeneral Procedures D, AAAA, BBBB, or CCCC or by methods known to oneskilled in the art (for example, the books from Larock, R. C. or Greene,T. W. and Wuts, P. G. M. referenced above) to givepyrrolotriazolopyrazines 38 as final products or intermediates (SchemeVI, step g). The pyrrolotriazolopyrazines 38 may be SEM protected(Scheme VI, step h) using conditions such as those described in GeneralProcedure KK, or as described in Greene, T. W. and Wuts, P. G. M.referenced above. If the R″ group in pyrrolotriazolopyrazines 37 or 39is a protecting group, it may be deprotected to yield alcohols 40(Scheme VI, step k) or 43 (Scheme VI, step i), respectively, usingconditions such as those described in Greene, T. W. and Wuts, P. G. M.referenced above. For example, a protecting group such as ap-methoxybenzyl (PMB) group can be removed from a PMB-ether to yield theunprotected alcohol (for example General Procedure FF) and thedeprotected compounds 40 or 43 may then be reacted further. Mitsunobureaction of alcohols 40 or 43 may be used to prepare ethers or esters 41(Scheme VI, step 1), 44 (Scheme VI, step j), or 45 (Scheme VI, step n)with inversion at the reacting center using conditions such as thosedescribed in General Procedure II or by methods known to one skilled inthe art such as those found in Larock, R. C. referenced above.Additionally, ethers 44 may be prepared from alcohols 43 via alkylationusing conditions such as those described in General Procedure HHHHAlternatively, alcohols 40 or 43 may be converted to carbamates 41 or 44using well-known conditions such as those described in GeneralProcedures OOO, WWW and PPPP. Removal of the sulfonamide protectinggroup of pyrrolotriazolopyrazines 41 may be accomplished usingconditions such as those described in General Procedures D, AAAA, BBBB,CCCC or PPPP, or by methods known to one skilled in the art (forexample, the books from Larock, R. C. or Greene, T. W. and Wuts, P. G.M. referenced above) to give pyrrolotriazolopyrazines 42 (Scheme VI,step m). The ester group of esters 45 may by cleaved to yield theunprotected alcohols 46 (Scheme VI, step o) using conditions such asthose described in General Procedure SS. The alcohols 46 can be reactedfurther to form ethers 44 (Scheme VI, step p) via Mitsunobu chemistry(in a manner as described for Scheme VI, step j) or by conditions suchas those described in General Procedure EE (which may require firstmaking the 2,2,2-trichloroimidate as described in General Procedure UU)or JJ or by methods known to one skilled in the art (for example, thebook from Larock, R. C. referenced above). The SEM protecting group ofpyrrolotriazolopyrazines 44 may be removed by methods such as thosedescribed in General Procedures LL and LL.1, or using conditions such asdescribed in Greene, T. W. and Wuts, P. G. M. referenced above to givepyrrolotriazolopyrazines 42 (Scheme VI, step q).

An alternate method for preparing ether-substituted1-cyclopentyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine compoundsof the invention is illustrated in Scheme VII. As shown in step a, theester of compounds 33 may be hydrolyzed under aqueous base or acidconditions to give the desired carboxylic acids 47, using conditionssuch as those described in General Procedures Z or TT or Larock, R. C.referenced above. The formation of lactones 48 from carboxylic acids 47(Scheme VII, step b) may be accomplished by methods such as thosedescribed in Example #4, General Procedure GG, or by methods known toone skilled in the art such as those found in Larock, R. C. referencedabove. The formation of hydrazides 49 from hydrazinylpyrrolopyrazines 5and lactones 48 (Scheme VII, step c) may be accomplished by a variety ofmethods known to one skilled in the art such as those described inExample #4 or General Procedure HH. The alcohols 49 may be reacted toform ethers 50 (Scheme VII, step d) using conditions such as thosedescribed in General Procedures VV (which may require first making the2,2,2-trichloroimidate as described in General Procedure UU) or JJ, orby methods known to one skilled in the art (for example, Tet. Lett.1983, 24(48), 5363). Mitsunobu reaction of alcohols 49 may be used toprepare ethers 51 (Scheme VII, step f) with inversion at the reactingcenter using conditions such as those described in Example #4, GeneralProcedure II, or by methods known to one skilled in the art such asthose found in Larock, R. C. referenced above. The hydrazides 50 or 51may be cyclized to pyrrolotriazolopyrazines 37 (Scheme VII, step e) or41 (Scheme VII, step g) using conditions such as those described inExample #4, General Procedures B or ZZZZ, or by methods known to oneskilled in the art (for example, Bioorganic & Medicinal ChemistryLetters 2007, 17(12), 3373-3377 or Journal of Medicinal Chemistry 1990,33(9), 2326-2334). Further elaboration of 37 or 41 may be performed asdescribed in Scheme VI.

Methods for preparing 1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridinecompounds of the invention are illustrated in Scheme VIII. As shown instep a, 4-chloro-3-iodopyridin-2-amine 52 may be nitrated to give4-chloro-3-iodo-5-nitropyridin-2-amine 53 as described in Example #21 orin Larock, R. C. “Comprehensive Organic Transformations: A Guide toFunctional Group Preparations, 2^(nd) edition”, 1999, Wiley-VCH.4-Chloro-3-iodo-5-nitropyridin-2-amine 53 is reacted with a(trimethylsilyl)acetylene via a Sonogashira cross coupling using methodsknown to one skilled in the art (for example Example #21 orWO2006058120A1) to give4-chloro-5-nitro-3-((trimethylsilyl)ethynyl)pyridin-2-amine 54 (SchemeVIII, step b). As shown in step c,4-chloro-5-nitro-3-((trimethylsilyl)ethynyl)pyridin-2-amine 54 isdeprotected to give the 4-chloro-3-ethynyl-5-nitropyridin-2-amine 55 asdescribed in Example #21 or using methods known to one skilled in theart (for example, the books from Greene, T. W. and Wuts, P. G. M.“Protective Groups in Organic Synthesis, 3^(rd) Edition”, 1999,Wiley-Interscience or Larock, R. C. referenced above).4-Chloro-3-ethynyl-5-nitropyridin-2-amine 55 is cyclized, as shown instep d, to give 4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine 56 asdescribed in Example #21, or by methods known to one skilled in the art(for example, as described in WO2008004117). As shown in step e,amino-substituted 1H-pyrrolo[2,3-b]pyridines 57 are prepared usingmethods known to one skilled in the art (for example, Example #21 orLarock, R. C. referenced above). Diamino-substituted1H-pyrrolo[2,3-b]pyridines 58 (Scheme VIII, step f) are prepared fromthe reduction of nitro-containing 1H-pyrrolo[2,3-b]pyridines 57 usingmethods known to one skilled in the art (for example, Example #21,General Procedure BBB, or Larock, R. C. referenced above). As shown instep g, diamino-substituted 1H-pyrrolo[2,3-b]pyridines 58 can becyclized as described in Example #21 or General Procedure DDD to give1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridines 59. Furtherfunctionalization of the R group in1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridines 59 can be performed, ifdesired, using reactions known to one skilled in the art (for example,Larock, R. C. referenced above). For example, amides, ureas,sulfonamides, aryl amines, heteroaryl amines, sulfonyl ureas,substituted amines, squaramides, or guanidines can be prepared from1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine 59 with an R groupcontaining a primary or secondary amine (for example General ProceduresG, H, I, J, J.1, XXX, EEEE, K, K.1, L, DD, QQ, RR, YY, ZZ followed byAAA, CCC, YYY, X, X.1, TTTT, or EEEEE). Also, deprotection of the Rgroup in 1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridines 59 to yield anunprotected compound can be performed using conditions such as thosedescribed in Greene, T. W. and Wuts, P. G. M. referenced above or inGeneral Procedures E, E.1, F, F.1, Y, or BB. For example, a protectinggroup such as a benzyloxycarbonyl (Cbz) group can be removed from aprotected amine to yield the unprotected amine (for example GeneralProcedures F, F.1, or Y) and the deprotected compounds 59 may then bereacted further as described above. Alternatively, intermediates 56 or57 may be sulfonamide protected using reactions known to one skilled inthe art (for example, Greene, T. W. and Wuts, P. G. M. referenced aboveor General Procedure K.1) to give sulfonamides 134 and 135 respectively(Scheme VII, steps h and m). As shown in step i, amino-substituted1H-pyrrolo[2,3-b]pyridines 135 may also be prepared fromchloro-substituted 1H-pyrrolo[2,3-b]pyridines 134 using methods known toone skilled in the art (for example, Example #23 or Larock, R. C.referenced above). Diamino-substituted 1H-pyrrolo[2,3-b]pyridines 136are prepared from the reduction of nitro-containing1H-pyrrolo[2,3-b]pyridines 135 using methods known to one skilled in theart (for example, Example #23, General Procedure BBB, or Larock, R. C.referenced above). As shown in step k, diamino-substituted1H-pyrrolo[2,3-b]pyridines 136 can be cyclized as described in Example#23 or General Procedure DDD to give sulfonamide-protected1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridines 137. Deprotection ofthe sulfonamide of compounds 137 to yield1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridines 59 (Scheme VIII,step 1) can be performed using conditions such as those described inGreene, T. W. and Wuts, P. G. M. “Protective Groups in OrganicSynthesis, 3^(rd) Edition”, 1999, Wiley-Interscience, General ProceduresD, XXX, AAAA, BBBB, or CCCC or Example #23.

Methods for preparing substituted cyclopentyl amines 61 for use in thepreparation of compounds of the invention are illustrated in Scheme IX.In step a, carboxylic acids 32 are subjected to a Curtius rearrangementas described in General Procedure NNN to form isocyanates 60. Thehydrolysis of isocyanates 60 yields amines 61 (for example, GeneralProcedure OOO).

Methods for preparing4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanonesand their derivatives as compounds of the invention are illustrated inScheme X. In step a, ketones 28 are protected as ketals 62 usingconditions as described in General Procedure WW or as those described inGreene, T. W. and Wuts, P. G. M. referenced above. The ester ofcompounds 62 may be hydrolyzed under aqueous base conditions to give thedesired carboxylic acids 63 (Scheme X, step b), using conditions such asthose described in General Procedure Z or Larock, R. C. referencedabove. The formation of hydrazides 64 from hydrazinylpyrrolopyrazines 5and carboxylic acids 63 (Scheme X, step c) may be accomplished by avariety of methods known to one skilled in the art such as thosedescribed in General Procedure A or standard peptide coupling methodssuch as those found in Larock, R. C. referenced above. The hydrazides 64may be cyclized to pyrrolotriazolopyrazines 65 (Scheme X, step d) usingconditions such as those described in General Procedures B or ZZZZ or bymethods known to one skilled in the art (for example, Bioorganic &Medicinal Chemistry Letters 2007, 17(12), 3373-3377 or Journal ofMedicinal Chemistry 1990, 33(9), 2326-2334). Ketals 65 may bedeprotected to yield ketones 66 as described in Preparation #25 orGreene, T. W. and Wuts, P. G. M. referenced above. Deprotection of thesulfonamide protecting group of pyrrolotriazolopyrazines 66 may beaccomplished using conditions such as those described in GeneralProcedures D, AAAA, BBBB, or CCCC or by methods known to one skilled inthe art (for example, Greene, T. W. and Wuts, P. G. M. referenced above)to give pyrrolotriazolopyrazines 67 as final products or intermediates(Scheme X, step f). For example, step g illustrates the formation ofoxime ethers 68 from ketones 67 which may be accomplished usingconditions such as those described in General Procedure PPP or Larock,R. C. referenced above.

Methods for preparing acetic acid and acetamide derivatives from4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanonesas compounds of the invention are illustrated in Scheme XI. As shown instep a, Horner-Wadsworth-Emmons reaction of ketones 66 to give alkenes69 may be accomplished using procedures known to one skilled in the artsuch as those described in General Procedure III. Deprotection of thesulfonamide protecting group of pyrrolotriazolopyrazines 69 may beaccomplished using conditions such as those described in GeneralProcedures D, AAAA, BBBB, or CCCC or by methods known to one skilled inthe art (for example, Greene, T. W. and Wuts, P. G. M. referenced above)to give pyrrolotriazolopyrazines 70 (Scheme XI, step b). Hydrogenationof alkenes 70 as described in General Procedures W or W.1 yieldspyrrolotriazolopyrazines 71 (Scheme XI, step c). Hydrolysis of esters 71gives acids 72 (Scheme XI, step d) using well known conditions such asthose described in General Procedure Z. The acids 72 may be furtherreacted to give amides 73 as shown in step e using conditions such asthose described in General Procedure H.

Methods for preparing4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylaminesas compounds of the invention are illustrated in Scheme XII. As shown instep a, reductive amination of ketones 66 to give amines 74 may beaccomplished using well known conditions such as those described inGeneral Procedures X or X.1. Deprotection of the sulfonamide protectinggroup of pyrrolotriazolopyrazines 74 may be accomplished usingconditions such as those described in General Procedures D, AAAA, BBBB,or CCCC or by methods known to one skilled in the art (for example,Greene, T. W. and Wuts, P. G. M. referenced above) to givepyrrolotriazolopyrazines 75 (Scheme XII, step b).

Methods for preparing dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridinecompounds of the invention are illustrated in Scheme XIII. In step a,reaction of5-chloro-4-iodo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine 76 witha substituted aldehyde provides alcohols 77 using procedures such asthose described in Example #29, Example #30, or in WO2009152133.Preparation of ketones 78 (step b) can be accomplished by treatment ofalcohols 77 with an oxidizing agent by methods known to one skilled inthe art (for example, Example #29, Example #30, or Larock, R. C.referenced above). Ketones 78 can then be converted to hydrazones 79with the loss of the TIPS protecting group through reaction withhydrazine using conditions such as those described in Example #29,Example #30 or General Procedure XXXX. Cyclization of hydrazones 79 toprovide dihydropyrazolo[4,3-a]pyrrolo[2,3-b]pyridines 80 can beaccomplished via an intramolecular Buchwald-Hartwig cyclization (forexample, General Procedure XX or Organic Letters, 2008, 10(18),4109-4112). Further functionalization of the R′″ group indihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridines 80 can be performed, ifdesired, using reactions known to one skilled in the art (for example,Larock, R. C. referenced above). For example, amides, ureas,sulfonamides, aryl amines, heteroaryl amines, sulfonyl ureas,substituted amines, squaramides, or guanidines can be prepared fromdihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridines 80 with an R′″ groupcontaining a primary or secondary amine (for example, General ProceduresG, H, I, J, J.1, XXX, EEEE, K, K.1, L, DD, QQ, RR, YY, ZZ followed byAAA, CCC, YYY, X, X.1, TTTT, or EEEEE). Also, deprotection of the R′″group in dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridines 80 to yielddeprotected compounds 80 can be performed using conditions such as thosedescribed in Greene, T. W. and Wuts, P. G. M. referenced above or inGeneral Procedures E, E.1, F, F.1, Y, or BB and the deprotectedcompounds 80 may then be reacted further as described above.

Methods for preparing2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h][1,6]naphthyridine compounds of theinvention are illustrated in Scheme XIV. In step a, o-lithiation of4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine 81 followed bytrapping of the anion with ethyl chloro formate yields ethyl4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate82 using conditions described in Example #28. The removal of the TIPSgroup of 82 may be accomplished as shown in step b to give ethyl4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 83 using conditionswell known in the literature (for example, Greene, T. W. and Wuts, P. G.M. referenced above or Example #28). In step c, sulfonamide protectedcompounds 84 are prepared using reactions known to one skilled in theart (for example, Greene, T. W. and Wuts, P. G. M. referenced above orExample #28). As shown in step d, amino-substituted1H-pyrrolo[2,3-b]pyridines 85 are prepared using methods known to oneskilled in the art (for example, Example #28 or Larock, R. C. referencedabove). The reduction of esters 85 to alcohols 86 (Scheme XIV, step e)may be accomplished using conditions well known in the literature (forexample, Example #28 or Larock, R. C. referenced above). In step f,alcohols 86 are oxidized to aldehydes 87 using methods known to oneskilled in the art (for example, Example #28 or Larock, R. C. referencedabove). The Wittig reaction of aldehydes 87 with((1,3-dioxolan-2-yl)methyl)triphenylphosphonium bromide (Scheme XIV,step g) yields alkenes 88 using conditions such as those described inExample #28. Reduction of alkenes 88 may be accomplished usingconditions such as those described in Example #28 or General ProceduresW or W.1 (Scheme XIV, step h). The cyclization of aminoacetals 89 togive protected 2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h][1,6]naphthyridines90 is accomplished using conditions described in Example #28 (schemeXIV, step i). Deprotection of the sulfonamide protecting group of2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h][1,6]naphthyridines 90 may beaccomplished using conditions such as those described in GeneralProcedures D, AAAA, BBBB, or CCCC or by methods known to one skilled inthe art (for example, Greene, T. W. and Wuts, P. G. M. referenced above)to give 2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h][1,6]naphthyridines 91(Scheme XIV, step j). Further functionalization of the R′ group in2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h][1,6]naphthyridines 91 can beperformed, if desired, using reactions known to one skilled in the art(for example, Larock, R. C. referenced above). For example, amides,ureas, sulfonamides, aryl amines, heteroaryl amines, sulfonyl ureas,substituted amines, squaramides, or guanidines can be prepared from2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h][1,6]naphthyridines 91 with an R′group containing a primary or secondary amine (for example, GeneralProcedures G, H, I, J, J.1, XXX, EEEE, K, K.1, L, DD, QQ, RR, YY, ZZfollowed by AAA, CCC, YYY, X, X.1, TTTT, or EEEEE). Also, deprotectionof the R′ group in2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h][1,6]naphthyridines 91 to yielddeprotected compounds 91 can be performed using conditions such as thosedescribed in Greene, T. W. and Wuts, P. G. M. referenced above or inGeneral Procedures E, E.1, F, F.1, Y, or BB and the deprotectedcompounds 91 may then be reacted further as described above.

Methods for preparing substituted imidazo[1,5-a]pyrrolo[2,3-e]pyrazinescompounds of the invention are illustrated in Scheme XV. As shown instep a, imidazo[1,5-a]pyrrolo[2,3-e]pyrazines 19 may be halogenatedusing conditions such as those described in General Procedure MM to give3-halo-imidazo[1,5-a]pyrrolo[2,3-e]pyrazines 92. The3-halo-imidazo[1,5-a]pyrrolo-[2,3-e]pyrazines 92 may undergo a varietyof reactions known to one skilled in the art (for example, Larock, R. C.referenced above) including, but not limited to, cyanation as describedin General Procedure HHH (Scheme XVI, step c) or Suzuki couplingreactions such as those described in General Procedures UUU or VVV(Scheme XV, step b). Deprotection of the sulfonamide protecting group ofimidazo[1,5-a]pyrrolo[2,3-e]pyrazines 93 may be accomplished usingconditions such as those described in General Procedures D, UUU, AAAA,BBBB, or CCCC, or by methods known to one skilled in the art (forexample, Greene, T. W. and Wuts, P. G. M. referenced above) to giveimidazo[1,5-a]pyrrolo[2,3-e]pyrazines 94 (Scheme XV, step c).

Methods for preparing pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazinecompounds of the invention are illustrated in Scheme XVI.Pyrrolotriazolopyrazines 8 may be halogenated using conditions such asthose described in General Procedures GGG or GGG.1 to give8-halopyrrolotriazolo-pyrazines 95 (Scheme XVI, step a). In step b,8-halopyrrolotriazolopyrazines 95 may be protected with a SEM groupusing conditions known in the literature such as those found in Greene,T. W. and Wuts, P. G. M. referenced above or as in General Procedure KK.The resulting SEM-protected 8-halopyrrolotriazolopyrazines 96 mayundergo a variety of reactions known to one skilled in the art (forexample, Larock, R. C. referenced above) including, but not limited to,cyanation as described in General Procedure HHH (Scheme XVI, step c),Suzuki coupling reactions as described in Preparation #23, formation ofa carboxylic ester as described in General Procedure AAAAA, or Stillecoupling reactions as described in General Procedure CCCCC (Scheme XVI,step e). The resulting products 97 or 99 may be deprotected usingconditions such as those described in General Procedure LL, LL.1, or bymethods known to one skilled in the art (for example, Greene, T. W. andWuts, P. G. M. referenced above) to givepyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazines 98 or 100 (Scheme XV,steps d and f, respectively). Additionally, compounds 99 and 100 mayundergo further functionalization, if desired, using reactions known toone skilled in the art (for example, Larock, R. C. referenced above).For example, for R═CO₂Et, the compound may be hydrolyzed usingconditions such as those described in General Procedure D and thenundergo amide bond formation as described in General Procedure H.

Methods for preparing substituted4-(sulfonamidomethyl)cyclopentanecarboxylic acids 110 for use in thepreparation of compounds of the invention are illustrated in SchemeXVII. In step a, 5-substituted-bicyclo[2.2.1]hept-2-enes 101 areoxidized to dicarboxylic acids 102 using known conditions such as thosedescribed in Preparation #11, Bioorganic & Medicinal Chemistry, 2007,15, 7581, or Journal of Organic Chemistry, 1993, 58, 4745. Formation ofthe mono-esters 103 are achieved through the cyclic anhydride asdescribed in Preparation #11 (Scheme XVII, step b). The t-butyl esters104 are prepared in step c using standard condition such as thosedescribed in Preparation #11 or Larock, R. C. referenced above.Reduction of the methyl ester of compounds 104 to alcohols 105 isachieved using well known conditions such as those found in Preparation#21 (Scheme XVII, step d). The mesylates 106 are prepared as describedin Preparation #21 or by methods known to one skilled in the art (SchemeXVII, step e). As shown in step f, the mesylates 106 may be used to formazides 107 using well known conditions such as those described inPreparation #21 or Larock, R. C. referenced above (Scheme XVII, step f).The reduction of azides 107 to amines 108 is a standard transformationthat may be accomplished as described in Preparation #21 or usingconditions such as those described in General Procedure TTT or inLarock, R. C. referenced above (Scheme XVII, step g). Step h shows theformation of sulfonamides 109 from amines 108 which is achieved asdescribed in General Procedures K or K.1 or by methods known to oneskilled in the art (for example, Greene, T. W. and Wuts, P. G. M.referenced above). The acidic cleavage of t-butyl esters 109 to give4-(sulfonamidomethyl)cyclo-pentanecarboxylic acids 110 (Scheme XVII,step i) may be done with the conditions described in General ProcedureQQQ or with methods known to one skilled in the art (for example, thebooks from Larock, R. C. or Greene, T. W. and Wuts, P. G. M. referencedabove).

Methods for preparing4-((dibenzylamino)methyl)-2-substituted-cyclopentanecarboxylic acids 115for use in the preparation of compounds of the invention are illustratedin Scheme XVIII. Reduction of the methyl ester of compounds 103 toalcohols 111 is achieved using well known conditions such as those foundin Preparation #22 or Larock, R. C. referenced above (Scheme XVIII, stepa). Step b illustrates the formation of esters 112 which is achieved asdescribed in Preparation #22 or Larock, R. C. referenced above. In stepc, alcohols 112 are oxidized to aldehydes 113 using known conditionssuch as those described in Preparation #22 or Larock, R. C. referencedabove. The reductive amination of aldehydes 113 using conditions such asthose described in General Procedures X or X.1 gives amines 114 (SchemeXVIII, step d). In step e, esters 114 are hydrolyzed to give4-((dibenzylamino)methyl)-2-substituted-cyclopentane-carboxylic acids115 using conditions such as those described in General Procedures Z orTT or known to one skilled in the art (for example, the books fromLarock, R. C. or Greene, T. W. and Wuts, P. G. M. referenced above).

Methods for preparing 3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-aminecompounds of the invention are illustrated in Scheme XIX. Alkylation ofpyrrolopyrazin-2-ylcarbamates 11 with t-butyl 2-bromoacetate, by methodsknown to one skilled in the art (for example, General Procedures S orS.1), gives pyrrolopyrazines 116 (Scheme XIX, step a). The doubledeprotection of pyrrolopyrazines 116 to aminoacetic acids 117 may beaccomplished using conditions such as those described in GeneralProcedures E, E.1, or QQQ (Scheme XIX, step b). The coupling of acids117 with amines provides amides 118 (Scheme XIX, step c) using wellknown conditions such as those given in General Procedure H or Larock,R. C. referenced above. As shown in step d, the cyclization of amides118 to imidazopyrrolopyrazin-8-amines 119 may be accomplished usingconditions such as those described in General Procedures OO or OO.1.Further functionalization of the R′ or R″ group inimidazopyrrolopyrazin-8-amines 119 can be performed, if desired, usingreactions known to one skilled in the art (for example, Larock, R. C.referenced above). For example, amides, ureas, sulfonamides, arylamines, heteroaryl amines, sulfonyl ureas, substituted amines,squaramides, or guanidines can be prepared fromimidazopyrrolopyrazin-8-amines 119 with an R′ or R″ group containing aprimary or secondary amine (for example, General Procedures G, H, I, J,J.1, XXX, EEEE, K, K.1, L, DD, QQ, RR, YY, ZZ followed by AAA, CCC, YYY,X, X.1, TTTT, or EEEEE). Also, deprotection of the of the R′ or R″ groupin imidazopyrrolopyrazin-8-amines 119 to yield deprotected compounds 119can be performed using conditions such as those described in Greene, T.W. and Wuts, P. G. M. referenced above or in General Procedures E, E.1,F, F.1, Y, or BB and the deprotected compounds 119 may then be reactedfurther as described above. Removal of the sulfonamide protecting groupof imidazopyrrolopyrazin-8-amines 119 may be accomplished usingconditions such as those described in General Procedures D, XXX, AAAA,BBBB, or CCCC or by methods known to one skilled in the art (forexample, the books from Larock, R. C. or Greene, T. W. and Wuts, P. G.M. referenced above) to give imidazopyrrolopyrazin-8-amines 120 (SchemeXIX, step e).

Methods for preparing pyrrolidine-3-carboxylic acids 125 for use in thepreparation of compounds of the invention are illustrated in Scheme XX.In step a, alkynes 121 are reduced to alkenes 122 as described inGeneral Procedure RRR or using methods known to one skilled in the art(for example, Larock, R. C. referenced above). The 1,3-dipolarcycloaddition of alkenes 122 andN-substituted-1-methoxy-N-((trimethylsilyl)methyl)methanamine 123 togive pyrrolidines 124 (Scheme XX, step b) can be accomplished by methodsknown to one skilled in the art (for example, General Procedure SSS orJournal of Medicinal Chemistry, 2009, 52(24), 7946-7949). The ester ofcompounds 124 may be hydrolyzed under aqueous base or acid conditions togive carboxylic acids 125 (Scheme XX, step c) using conditions such asthose described in General Procedures Z or TT or Larock, R. C.referenced above.

Methods for preparing sulfone-substituted1-cyclopentyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine compoundsof the invention are illustrated in Scheme XXI. As shown in step a,Mitsunobu reaction of alcohols 46 with appropriate thiols gives sulfides126 using conditions such as those described in General Procedure MMM orby methods known to one skilled in the art (for example, Larock, R. C.referenced above). The oxidation of sulfides 126 to sulfones 127 (SchemeXXI, step b) is accomplished as described in General Procedure LLL or bymethods known to one skilled in the art (for example, Larock, R. C.referenced above). The SEM protecting group of pyrrolotriazolopyrazines127 may be removed by methods such as those described in GeneralProcedures LL and LL.1, or using conditions such as described in Greene,T. W. and Wuts, P. G. M. referenced above to givepyrrolotriazolopyrazines 128 (Scheme XXI, step c).

Methods for preparing sulfonyl chlorides 133 for use in the preparationof compounds of the invention are illustrated in Scheme XXII. In step a,sulfonates 130 are prepared from sulfonyl chlorides 129 using knownreaction conditions such as those described in Preparation #6 Step A,WO2007014011, or WO2009018238. An additional substitutent is added tosulfonates 130 to give sulfonates 131 via alkylation as described inGeneral Procedure KKK, WO2007014011, or WO2009018238 (Scheme XXII, stepb). In step c, potassium sulfonates 132 are prepared from sulfonates 131with aqueous potassium cyanate using conditions such as those in GeneralProcedure JJJ, WO2007014011, or WO2009018238. Potassium sulfonates 132are converted to sulfonyl chlorides 133 (Scheme XXII, step d) usingthionyl chloride as described in General Procedure EEE, WO2007014011, orWO2009018238.

Methods for preparing imidazopyrrolo[2,3-e]pyrazines compounds of theinvention are illustrated in Scheme XXIII. Imidazopyrrolopyrazines 15[T=N, U═CH] or 20 [T=CH, U═N] may be halogenated using conditions suchas those described in General Procedures GGG or GGG.1 to give8-haloimidazopyrrolopyrazines 138 (Scheme XXIII, step a). In step b,8-haloimidazopyrrolopyrazines 138 may be protected with a SEM groupusing conditions known in the literature such as those found in Greene,T. W. and Wuts, P. G. M. referenced above or as in General Procedure KK.The resulting SEM-protected 8-haloimidazopyrrolopyrazines 139 mayundergo a variety of reactions known to one skilled in the art (forexample, Larock, R. C. referenced above) including, but not limited to,cyanation as described in General Procedure HHH (Scheme XXIII, step c)or Suzuki coupling reactions as described in General Procedure VVV orStille coupling reactions as described in General Procedure CCCCC(Scheme XXIII, step e). The resulting products 140 or 142 may bedeprotected using conditions such as those described in GeneralProcedures LL and LL.1, or by methods known to one skilled in the art(for example, Greene, T. W. and Wuts, P. G. M. referenced above) to giveimidazopyrrolo[2,3-e]pyrazines 141 or 143 (Scheme XXIII, steps d and f,respectively).

Methods for preparing compounds of the invention from a common ketoneintermediate are illustrated in Scheme XXIV. As shown in scheme XXIV,step a, ketones 144 may be reacted with an alkyl lithium or a Grignardreagent to give alcohols 145 using conditions known to one skilled inthe art (for example, Larock, R. C. referenced above or GeneralProcedure ZZZ). Alternatively, ketones 144 may undergo aHorner-Wadsworth-Emmons reaction with a reagent such as ethyl2-(diethoxyphosphoryl)acetate (R′″═CO₂Et) or diethylcyanomethylphosphonate (R′″═CN) as described in General Procedure III togive alkenes 146 (Scheme XXIV, step b). Alkenes 146 may be hydrogenatedto alkanes 147 using well-known conditions such as those described inGeneral Procedure W and W.1 (Scheme XXIV, step c). The R′″ group may befurther functionalized using a variety of reactions such as thosedescribed in Larock, R. C. referenced above. For example, for R′″═CO₂Et,alcohols 148 can be prepared as described in General Procedure ZZZ(Scheme XXIV, step d) or oxadiazoles 149 may be prepared as described inGeneral Procedure DDDD (Scheme XXIV, step e). As shown in scheme XXIV,step f, ketones 144 may also be reduced to alcohols 150 as described inGeneral Procedure P or in Larock, R. C. referenced above. Mesylates 151are formed from alcohols 150 using conditions known to one skilled inthe art such as those described in General Procedure IIII (Scheme XXIV,step g) and can be reacted with a variety of nucleophiles (Nu) asdescribed in General Procedure JJJJ (Scheme XXIV, step h) to givecompounds 152. Depending on the nucleophile used, furtherfunctionalization can be done to give compounds 153 (Scheme XXIV, stepi). These functionalizations may be accomplished using methods such asthose described in Larock, R. C. referenced above or General ProceduresQQQQ or UUUU.

Methods for preparing1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-amine compounds of theinvention are illustrated in Scheme XXV. Diamines 136 (Scheme XVIII) maybe reacted with cyanogen bromide as described in General Procedure RRRR(Scheme XXV, step a). The resulting1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-amines 154 may befurther further functionalized, if desired, using reactions known to oneskilled in the art (see, for example, Larock, R. C. above) to give1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-amines 155 (Scheme XXV,step b). Removal of the sulfonamide protecting group of1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-amines 155 or 154 maybe accomplished using conditions such as those described in GeneralProcedures D, AAAA, BBBB, or CCCC or by methods known to one skilled inthe art (for example, the books from Larock, R. C. or Greene, T. W. andWuts, P. G. M. referenced above) to give1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-amines 156 or 157,respectively (Scheme XXV, steps c and d).

Methods for preparing1,6-dihydropyrrolo[2,3-b][1,2,3]triazolo[4,5-d]pyridine compounds of theinvention are illustrated in Scheme XXV. Diamines 136 (Scheme XVIII) maybe reacted with sodium nitrite as described in General Procedure SSSS togive 1,6-dihydropyrrolo[2,3-b][1,2,3]triazolo[4,5-d]pyridines 158(Scheme XXVI, step a). Removal of the sulfonamide protecting group of1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-amines 158 may beaccomplished using conditions such as those described in GeneralProcedures D, AAAA, BBBB, or CCCC or by methods known to one skilled inthe art (for example, the books from Larock, R. C. or Greene, T. W. andWuts, P. G. M. referenced above) to give1,6-dihydropyrrolo[2,3-b][1,2,3]triazolo[4,5-d]pyridines 159 (SchemeXXV, step b).

Alternate methods for preparing the ketone intermediate used to makedihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine compounds of the inventionare illustrated in Scheme XXVII. In step a, carboxylic acids 160 areconverted to the corresponding acid chlorides 161 using conditionswidely known to one skilled in the art such as those described inGeneral Procedure WWWW. Acid chlorides 161 are reacted with5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine 162 asdescribed in General Procedure VVVV (Scheme XXVII, step b) to giveketones 78 which may be further reacted as described in Scheme XIII.

Alternate methods for preparing imidazo[1,2-a]pyrrolo[2,3-e]pyrazinescompounds of the invention are illustrated in Scheme XXVIII. In step a,carboxylic acids 160 are converted to the corresponding sulfoxoniumylides 163 using conditions such as those described in General ProcedureFFFFF or J. Org. Chem. 2004, 69, 1629. Pyrrolopyrazin-2-amines 164 maybe prepared from pyrrolopyrazin-2-ylcarbamates 11 (Scheme II) usingconditions known to one skilled in the art such as those described inGeneral Procedure E or Greene, T. W. and Wuts, P. G. M. referenced above(Scheme XXVIII, step b). Sulfoxonium ylides 163 are reacted withpyrrolopyrazin-2-amines 164 using conditions such as those described inGeneral Procedure GGGGG or Org. Lett. 2009, 11, 3566 to givepyrrolopyrazines 13 which may be further reacted as described in SchemeII (Scheme XXVIII, step c). Alternatively, as shown in step d,pyrrolopyrazin-2-amines 164 may be reacted with an α-haloaldehyde usingconditions such as those given in General Procedure YYYY to giveimidazopyrrolopyrazines 14 which may be further reacted as described inScheme II.

If desired, chiral separation of any of the chiral compounds in SchemesI-XXVIII may be done using methods known to one skilled in the art suchas chiral preparative HPLC or chiral SFC (for example, General ProcedureAA) or crystallization of diastereomeric salts as described in Example#5. Further functionalization of any of the R groups above (e.g. R, R″,R′″, R″″, and R′″″) can be performed, if desired, using reactions knownto one skilled in the art (for example, Larock, R. C. referenced above).For example, formation of amides, ureas, sulfonamides, aryl amines,heteroaryl amines, sulfonyl ureas, substituted amines, squaramides, orguanidines can be prepared with an R group containing a primary orsecondary amine (for example, General Procedures G, H, I, J, J.1, XXX,EEEE, K, K.1, L, DD, QQ, RR, YY, ZZ followed by AAA, CCC, YYY, X, X.1,TTTT, or EEEEE). Also, deprotection of an R group to yield deprotectedcompounds may be performed using conditions such as those described inGreene, T. W. and Wuts, P. G. M. referenced above or in GeneralProcedures E, E.1, F, F.1, Y, or BB and the deprotected compounds maythen be reacted further as described above.

General Procedures and Examples

The general synthetic schemes that were utilized to construct themajority of compounds disclosed in this application are described belowin Schemes 1-111. These schemes are provided for illustrative purposesonly and are not to be construed as limiting the scope of the invention.

Scheme 67: Hydrolysis of an Isocyanate (General Procedure OOO)

R—N═C═O→R—NH₂

Scheme 99: Reduction of an Azide to an Amine (General Procedure UUUU)

R—N₃→R→NH₂

Scheme 107: Stille Coupling of an Aryl or Heteroaryl Halide (GeneralProcedure CCCCC)

R—X+R′Sn(R″)₃→R—R′

List of General Procedures

-   General Procedure A Formation of a hydrazide from a carboxylic acid-   General Procedure B Cyclization of a hydrazide-   General Procedure C Cyclization of a hydrazide with loss of    Boc-protecting group-   General Procedure D Hydrolysis of a sulfonamide-   General Procedure E Acidic cleavage of a Boc-protected amine-   General Procedure E.1 Acidic cleavage of a Boc-protected amine-   General Procedure F Deprotection of a Cbz-protected amine using HBr    in AcOH-   General Procedure G Formation of an acetamide-   General Procedure H Formation of an amide from a carboxylic acid and    an amine-   General Procedure I Formation of a urea from an amine and a    carbamoyl chloride-   General Procedure J Formation of a urea or thiourea using CDI or    thiocarbonyl diimidazole, respectively-   General Procedure K Formation of a sulfonamide from an amine-   General Procedure K.1 Formation of a sulfonamide from an amine or    nitrogen containing heterocycle-   General Procedure L Displacement of an aryl or heteroaryl halide    with an amine-   General Procedure M Boc-protection of an amine-   General Procedure M.1 Boc-protection of a nitrogen-containing    compound-   General Procedure N Cbz-protection of an amine-   General Procedure O Reduction of a pyridine-   General Procedure P Reduction of carbonyl to an alcohol-   General Procedure Q Cyclization of an amide using a    dithiaphosphetane reagent-   General Procedure R Formation of a bromomethyl ketone from an acid-   General Procedure S N-Alkylation using an alkyl halide or    α-haloketone-   General Procedure T Cyclization of a ketone using a    dithiaphosphetane reagent-   General Procedure U Knoevenagel condensation to form a substituted    cyclopentadiene-   General Procedure V Decarboxylation of a β-ketoester enolate-   General Procedure W Hydrogenation of an alkene-   General Procedure W.1 Hydrogenation of an alkene-   General Procedure X Reductive amination of a ketone or aldehyde-   General Procedure X.1 Reductive amination of a ketone or aldehyde-   General Procedure Y Hydrogenation of a benzyl- or Cbz-protected    amine-   General Procedure Z Basic hydrolysis of an ester to a carboxylic    acid-   General Procedure AA Chiral preparative HPLC separation of    stereoisomers-   General Procedure BB Acidic hydrolysis of an acetyl protected amine-   General Procedure CC Formation of a sulfamoyl chloride-   General Procedure DD Formation of a sulfonylurea-   General Procedure EE Ether formation from a trichloroacetimidate    derivative-   General Procedure FF Deprotection of a PMB-protected alcohol-   General Procedure GG Formation of a lactone-   General Procedure HH Opening of a lactone with an amine or hydrazine-   General Procedure II Mitsunobu reaction of an alcohol-   General Procedure JJ Displacement of a halide with an alcohol-   General Procedure KK SEM protection of a nitrogen-   General Procedure LL SEM deprotection of a nitrogen-   General Procedure MM Halogenation of an imidazole-   General Procedure NN Formation of an amide from a carboxylic acid    and an amine with loss of a sulfonamide protecting group-   General Procedure OO Cyclization with POCl₃-   General Procedure OO.1 Cyclization with POCl₃-   General Procedure PP Reaction of an amine with an aryl boronic acid-   General Procedure QQ Formation of a urea from an amine and an    isocyanate-   General Procedure RR Formation of a urea from an amine, a heteroaryl    amine and phenyl chloroformate-   General Procedure SS Hydrolysis of an ester to an alcohol-   General Procedure TT Acid-mediated conversion of an ester to a    carboxylic acid-   General Procedure UU Formation of a 2,2,2-trichloroacetimidate-   General Procedure VV Formation of a TBDMS-protected alcohol-   General Procedure WW Formation of a ketal-   General Procedure XX Palladium catalyzed coupling of a hydrazone-   General Procedure YY Michael addition of an amine to an    α,β-unsaturated sulfonamide-   General Procedure ZZ Formation of an oxazolidinone sulfonourea-   General Procedure AAA Formation of a sulfonylurea from an    oxazolidinone sulfonourea-   General Procedure BBB Reduction of a nitro group-   General Procedure CCC Formation of an amide-   General Procedure DDD Cyclization to form a fused imidazole-   General Procedure EEE Formation of a sulfonyl chloride-   General Procedure FFF Generation of an ether under reductive    conditions-   General Procedure GGG Iodination, chlorination or bromination of a    heterocycle or halogenation of a heterocycle-   General Procedure GGG.1 Iodination of a heterocycle or halogenation    of a heterocycle-   General Procedure HHH Cyanation of a heterocycle-   General Procedure III Horner-Wadsworth-Emmons reaction of a ketone-   General Procedure JJJ Formation of a potassium sulfonate-   General Procedure KKK Alkylation of a sulfonate-   General Procedure LLL Oxidation of a thioether to a sulfone-   General Procedure MMM Mitsunobu reaction using a thiol-   General Procedure NNN Curtius reaction to form an isocyanate-   General Procedure OOO Hydrolysis of an isocyanate-   General Procedure PPP Formation of an oxime ether from a ketone-   General Procedure QQQ TFA-mediated conversion of a t-butyl ester to    a carboxylic acid-   General Procedure RRR Reduction of an alkyne to an alkene-   General Procedure SSS 1,3-Dipolar cycloaddition to form a    pyrrolidine-   General Procedure TTT Hydrogenation of an azide to an amine-   General Procedure UUU Reaction of an aryl or heteroaryl halide with    a boronic acid or boronate ester followed by tosyl deprotection-   General Procedure VVV Reaction of an aryl or heteroaryl halide with    a boronic acid or boronate ester-   General Procedure WWW Formation of a carbamate-   General Procedure XXX Urea formation with loss of protecting group-   General Procedure YYY Michael addition-   General Procedure ZZZ Grignard or alkyl lithium addition to a    carbonyl-containing compound-   General Procedure AAAA Deprotection of a sulfonamide with DBU-   General Procedure BBBB Deprotection of a sulfonamide with TBAF-   General Procedure CCCC Deprotection of a sulfonamide with KCN-   General Procedure DDDD Formation of an oxadiazole-   General Procedure EEEE Formation of a urea using phosgene-   General Procedure FFFF Formation of an amide from an ester-   General Procedure GGGG Formation of a nitrile from a primary amide-   General Procedure HHHH O-alkylation with KOH or NaOH and TBAB-   General Procedure IIII Formation of a mesylate-   General Procedure JJJJ Displacement of an alkyl mesylate, tosylate,    or halide with a nucleophile-   General Procedure KKKK Cyclization of a ketone using TFAA or PFPAA-   General Procedure LLLL Formation of a bromoketone from a ketone or    an aldehyde-   General Procedure MMMM Formation of a ketone from a Weinreb amide-   General Procedure NNNN Formation of β-hydroxysulfonamide from a    ketone-   General Procedure OOOO Formation of a phenyl carbonate-   General Procedure PPPP Formation of a carbamate followed by    sulfonamide hydrolysis-   General Procedure QQQQ Oxidation of an alkyl thioacetate to an alkyl    sulfonic acid-   General Procedure RRRR Cyclization of a diamine with cyanogen    bromide-   General Procedure SSSS Cyclization of a diamine with NaNO₂-   General Procedure TTTT Formation of a squaramide-   General Procedure UUUU Reduction of an azide to an amine-   General Procedure VVVV Formation of a ketone from a heteroaryl    halide-   General Procedure WWWW Formation of an acid chloride-   General Procedure XXXX Formation of a hydrazone-   General Procedure YYYY Cyclization with an α-haloaldehyde-   General Procedure ZZZZ Cyclization of a hydrazide followed by    hydrolysis of a sulfonamide-   General Procedure AAAAA Formation of a carboxylic acid or ester from    an aryl halide-   General Procedure BBBBB Cyclization with an orthoformate-   General Procedure CCCCC Stille coupling of an aryl or heteroaryl    halide-   General Procedure DDDDD Deprotection of a Cbz-protected amine using    triethylsilane-   General Procedure EEEEE Formation of a guanidine-   General Procedure FFFFF Formation of a sulfoxonium ylide-   General Procedure GGGGG Reaction of a sulfoxonium ylide with an    amine

The following examples are ordered according to the final generalprocedure used in their preparation. The synthetic routes to any novelintermediates are detailed by sequentially listing the general procedure(letter codes) in parentheses after their name with additional reactantsor reagents as appropriate. A worked example of this protocol is givenbelow using Preparation #Z.1 as a non-limiting illustration. Preparation#Z.1 is(1S,2R,4S)-4-(cyclopropanesulfonamido)-2-ethylcyclopentane-carboxylicacid, which was prepared from (1S,2R,4S)-ethyl4-(cyclopropanesulfonamido)-2-ethylcyclopentane carboxylate usingGeneral Procedure Z as represented in Scheme A.

The precursor to Preparation #Z.1, (1S,2R,4S)-ethyl4-(cyclopropanesulfonamido)-2-ethylcyclopentane-carboxylate, wasprepared (as shown in Scheme B) by initially reacting ethyl4-amino-2-ethylcyclopentanecarboxylate (Preparation #Y.1) with thecommercially available cyclopropanesulfonyl chloride, following theconditions given in General Procedure K, to give ethyl4-(cyclopropanesulfonamido)-2-ethylcyclopentane-carboxylate as a mixtureof stereoisomers. This mixture of stereoisomers is separated asdescribed in General Procedure AA, using the conditions from Method 1 inTable 2, to give the precursor to Preparation #Z.1, (1S,2R,4S)-ethyl4-(cyclopropanesulfonamido)-2-ethylcyclopentane-carboxylate as a singleenantiomer with a retention time of 9.5 minutes and a negative opticalrotation. The reaction sequence to synthesize the precursor toPreparation #Z.1, (1S,2R,4S)-ethyl4-(cyclopropanesulfonamido)-2-ethylcyclopentane-carboxylate, (detailedabove) is consequently translated in the preparations and examplessection to: (1S,2R,4S)-ethyl4-(cyclopropanesulfonamido)-2-ethylcyclopentane-carboxylate (preparedusing K from Preparation #Y.1 and cyclopropanesulfonyl chloride, AA[Table 2, Method 1, R_(t)=9.5 min, or =negative]). Hence the Preparation#Z.1 would be written as: Preparation #Z.1 was prepared from(1S,2R,4S)-ethyl 4-(cyclopropanesulfonamido)-2-ethylcyclopentanecarboxylate (prepared using K from Preparation #Y.1 andcyclopropanesulfonyl chloride, AA [Table 2, Method 1, R_(t)=9.5 min, or=negative]) using General Procedure Z.

Analytical Methods

Analytical data was included within the procedures below, in theillustrations of the general procedures, or in the tables of examples.Unless otherwise stated, all ¹H NMR data were collected on a VarianMercury Plus 400 MHz or a Varian Inova 600 MHz instrument and chemicalshifts are quoted in parts per million (ppm). LC/MS and HPLC data arereferenced to the table of LC/MS and HPLC conditions using the lowercase method letter provided in Table 1.

TABLE 1 LC/MS and HPLC methods Method Conditions a LC/MS: The gradientwas 5-60% B in 1.5 min then 60-95% B to 2.5 min with a hold at 95% B for1.2 min (1.3 mL/min flow rate). Mobile phase A was 10 mM NH₄OAc, mobilephase B was HPLC grade MeCN. The column used for the chromatography is a4.6 × 50 mm MAC-MOD Halo C18 column (2.7 μm particles). Detectionmethods are diode array (DAD) and evaporative light scattering (ELSD)detection as well as positive/negative electrospray ionization. b LC/MS:The gradient was 5-60% B in 1.5 min then 60-95% B to 2.5 min with a holdat 95% B for 1.2 min (1.3 mL/min flow rate). Mobile phase A was 10 mMNH₄OAc, mobile phase B was HPLC grade MeCN. The column used for thechromatography is a 4.6 × 50 mm MAC-MOD Halo C8 column (2.7 μmparticles). Detection methods are diode array (DAD) and evaporativelight scattering (ELSD) detection as well as positive/negativeelectrospray ionization. c LC/MS: The gradient was 5-60% B in 0.75 minthen 60-95% B to 1.15 min with a hold at 95% B for 0.75 min (1.3 mL/minflow rate). Mobile phase A was 10 mM NH₄OAc, mobile phase B was HPLCgrade MeCN. The column used for the chromatography was a 4.6 × 50 mmMAC-MOD Halo C8 column (2.7 μm particles). Detection methods are diodearray (DAD) and evaporative light scattering (ELSD) detection as well aspositive/negative electrospray ionization. d HPLC: The gradient was5-100% B over 40 min, hold at 100% for 5 min, 2 min back to 5% B, holdat 5% B for 4 min (21 mL/min flow rate). Mobile phase A was 50 mM NH₄OAc(pH 4.5) and mobile phase B was HPLC grade MeCN. The column used for thechromatography was a 21.2 × 250 mm Hypersil C18 HS column (8 μmparticles). Detection method was UV. e HPLC: The gradient was 1-5% Bover 3 min then 5-55% B over 6 min with a hold at 55% B for 0.10 minthen 55-95% B over 1.5 min (22.5 mL/min flow rate). Mobile phase A was50 mM NH₄OAc (pH 4.5) and mobile phase B was HPLC grade MeCN, the columnused for the chromatography was a 19 × 50 mm Waters Atlantis T3 OBD C18column (5 μm particles), detection methods are Photodiode array DAD andWaters ZQ 2000 mass spectrometer. f HPLC: The gradient was 10-75% B over9 min with a hold at 75% for 0.10 min then 75%-100% B over 1.5 min (22.5mL/min flow rate). Mobile phase A was 50 mM NH4OAc (pH 4.5) and mobilephase B was HPLC grade MeCN, the column used for the chromatography wasa 19 × 50 mm Waters Atlantis T3 OBD C18 column (5 μm particles),detection methods were Photodiode array DAD and Waters ZQ 2000 massspectrometer. g HPLC: The gradient was 10% B over 2.5 min then 10-15% Bover 0.50 min then 15-75% B over 3 min then 75-85% B over 3.10 min then85%-100% B over 1.5 min (22.5 mL/min flow rate). Mobile phase A was 50mM NH₄OAc (pH 4.5) and mobile phase B was HPLC grade MeCN, the columnused for the chromatography was a 19 × 50 mm Waters Atlantis T3 OBD C18column (5 μm particles), detection methods were Waters 2996 photodiodearray DAD and Waters ZQ 2000 mass spectrometer. h HPLC: The gradient was10-85% B over 9.00 min then 85-95% B over 0.10 min then held at 95% Bfor 1.50 min (25.0 mL/min flow rate). Mobile phase A was 50 mM NH₄OAc(pH 4.5) and mobile phase B was HPLC grade MeCN, the column used for thechromatography was a 19 × 50 mm Waters Atlantis T3 OBD C18 column (5 μmparticles), detection methods were Waters 2996 photodiode array DAD andWaters ZQ 2000 mass spectrometer. i HPLC: The gradient was 10-35% B over45 min (25 mL/min flow rate). Mobile phase A was 50 mM NH₄OAc (pH 4.5)and mobile phase B was HPLC grade MeCN. The column used for thechromatography was a 21.2 × 250 mm Hypersil C18 HS column (8 μmparticles). Detection method was UV. j HPLC: The gradient was 5-75% Bover 25 min (21 mL/min flow rate). Mobile phase A was 50 mM NH₄OAc (pH4.5) and mobile phase B was HPLC grade MeCN. The column used for thechromatography was a 21.2 × 250 mm Hypersil C18 HS column (8 μmparticles). Detection method was UV. k HPLC: The gradient was 20-40% Bover 30 min (21 mL/min flow rate). Mobile phase A was 50 mM NH₄OAc (pH4.5) and mobile phase B was HPLC grade MeCN. The column used for thechromatography was a 21.2 × 250 mm Hypersil C18 HS column (8 μmparticles). Detection method was UV. l HPLC: The gradient was 0-100% Bover 30 min (21 mL/min flow rate). Mobile phase A was 50 mM NH₄OAc (pH4.5) and mobile phase B was HPLC grade MeCN. The column used for thechromatography was a 21.2 × 250 mm Hypersil C18 HS column (8 μmparticles). Detection method was UV. m HPLC: The gradient was 5% B, holdfor 5 min, 5-100% B over 40 min, hold at 100% for 5 min, 2 min back to5% B, hold at 5% B for 4 min, (21 mL/min flow rate). Mobile phase A was50 mM NH₄OAc (pH 4.5) and mobile phase B was HPLC grade MeCN. The columnused for the chromatography was a 21.2 × 250 mm Hypersil C18 HS column(8 μm particles). Detection method was UV. n LC/MS: The gradient was5-60% B in 0.60 min then 60-95% B to 1.0 min with a hold at 95% B for0.30 min (1.25 mL/min flow rate). Mobile phase A was 10 mM NH₄OAc,mobile phase B was HPLC grade MeCN. The column used for thechromatography is 2.1 × 30 mm Acquity UPLC HSS T3 column (1.8 μmparticles). Detection methods are diode array (DAD) and evaporativelight scattering (ELSD) detection as well as positive/negativeelectrospray ionization. o LC/MS: The gradient was 60-95% B in 1.15 minwith a hold at 95% B for 3 min (1.3 mL/min flow rate). Mobile phase Awas 10 mM NH₄OAc, mobile phase B was HPLC grade MeCN. The column usedfor the chromatography is a 4.6 × 50 mm MAC-MOD Halo C8 column (2.7 μmparticles). Detection methods are diode array (DAD) and evaporativelight scattering (ELSD) detection as well as positive/negativeelectrospray ionization. p LC/MS: The gradient was 5% B, hold for 0.2min, 5-95% B over 1.7 min, hold at 95% for 1.3 min, back to 5% B within0.01 min, (2.3 mL/min flow rate). Mobile phase A was water (0.05% TFA)and mobile phase B was HPLC grade MeCN (0.05% TFA). The column used forthe chromatography was a 4.6 × 50 mm XBridge C18 column (3.5 μmparticles). Temperature 50° C. Detection method was UV. q HPLC: Thegradient was 10-75% B over 10 min (22.5 mL/min flow rate). Mobile phaseA was 50 mM NH₄OAc (pH 4.5) and mobile phase B was HPLC grade MeCN, thecolumn used for the chromatography was a 19 × 50 mm Waters Atlantis T3OBD C18 column (5 μm particles), detection methods were Photodiode arrayDAD and Waters ZQ 2000 mass spectrometer. r LC/MS: The gradient was80-65% B in 1.80 min then 65-40% B to 2.80 min with a hold at 40% foranother 1.20 min (1.3 mL/min flow rate). The column used for thechromatography is a 4.6 × 50 mm X-bridge hilic column (3.5 μmparticles). Mobile phase A was 10 mM ammonium acetate, mobile phase Bwas HPLC grade acetonitrile. Detection methods are diode array (DAD) andevaporative light scattering (ELSD) detection as well aspositive/negative electrospray ionization. s HPLC: The gradient was0-100% B over 15 min, hold at 100% for 15 min (21 mL/min flow rate).Mobile phase A was 50 mM NH₄OAc (pH 4.5) and mobile phase B was HPLCgrade MeCN. The column used for the chromatography was a 21.2 × 250 mmHypersil C18 HS column (8 μm particles). Detection method was UV. tHPLC: The gradient was 24% B over 2 min then 24-55% B over 7.6 min then55-98% B over 1 min (25 mL/min flow rate). Mobile phase A was 50 mMNH₄OAc (pH 4.5) and mobile phase B was HPLC grade MeCN, the column usedfor the chromatography was a 19 × 50 mm Waters Atlantis T3 OBD C18column (5 μm particles), detection methods were Waters 2996 photodiodearray DAD and Waters ZQ 2000 mass spectrometer. u LC/MS: The gradientwas 0-0.1 min 10% A, 0.1-1.1 min 10-100% A, 1.1-1.3 min 100% A, then1.3-1.4 min 100-10% A. Flow rate was 1 mL/min. Mobile phase A was HPLCgrade acetonitrile and mobile phase B was 0.1% trifluoroacetic acid inwater. The column used was a Waters BEH C8, 1.7 μm (2.1 mm × 30 mm) at atemperature of 55° C. Detection methods were diode array (DAD) andevaporative light scattering (ELSD) detection as well as positive APCIionization. v The gradient was 0-0.1 min 10% A, 0.1-2.6 min 10-100% A,2.6-2.9 min 100% A, 2.9-3.0 min 100-10% A then 0.5 min post-run delay.Flow rate was 2 mL/min. Mobile phase A was HPLC grade acetonitrile andmobile phase B was 0.1% trifluoroacetic acid in water. The column usedfor the chromatography was a Phenomenex Luna Combi-HTS C8(2) 5 μm 100 Å(2.1 mm × 50 mm), at a temperature of 55° C. Detection methods werediode array (DAD) and evaporative light scattering (ELSD) detection aswell as positive APCI ionization. w HPLC: The gradient was 15% B over3.5 min then 15-46% B over 6.1 min then 46-98% B over 1.2 min (25 mL/minflow rate). Mobile phase A was 50 mM NH₄OAc (pH 4.5) and mobile phase Bwas HPLC grade MeCN, the column used for the chromatography was a 19 ×50 mm Waters Atlantis T3 OBD C18 column (5 micron particles), detectionmethods were Waters 2996 photodiode array DAD and Waters ZQ 2000 massspectrometer. x HPLC: The gradient was 0-80% B over 5 min, hold at 80%for 4 min, 0.1 min at 90% B, then 90 to 0% B for 2.9 min, hold at 0% Bfor 2 min (1 mL/min flow rate). Mobile phase A was 0.1% H₃PO₄ in waterand mobile phase B was HPLC grade MeCN. The column used for thechromatography was a 4.6 × 150 mm Ascentis Express column (2.8 μmparticles). Detection method was UV. y HPLC: The gradient was 0-50% Bover 45 min (25 mL/min flow rate). Mobile phase A was 50 mM NH₄OAc (pH4.5) and mobile phase B was HPLC grade MeCN. The column used for thechromatography was a 21.2 × 250 mm Hypersil C18 HS column (8 μmparticles). Detection method was UV.

TABLE 2 Chiral HPLC methods Method Conditions 1 Isocratic 50% A for 25min (20 mL/min flow rate). Mobile phase A was a 50:50 mixture of HPLCgrade MeOH and EtOH (200 proof), mobile phase B was HPLC grade heptanewith 0.1% diethylamine added. The column used for the chromatography wasa Daicel IA, 20 × 250 mm column (5 μm particles). Detection methods wereevaporative light scattering (ELSD) detection as well as opticalrotation. 2 Isocratic 100% EtOH (200 proof) for 13 min (10 mL/min flowrate). The column used for the chromatography was a Daicel IC, 20 × 250mm column (5 μm particles). Detection methods were evaporative lightscattering (ELSD) detection as well as optical rotation. 3 Isocratic 20%A for 10-23 min (20 mL/min flow rate). Mobile phase A was EtOH (200proof), mobile phase B was HPLC grade heptane with 0.12% diethylamineadded. The column used for the chromatography was a Daicel IC, 20 × 250mm column (5 μm particles). Detection methods were evaporative lightscattering (ELSD) detection as well as optical rotation. 4 Isocratic 70%A for 25 min (20 mL/min flow rate). Mobile phase A was EtOH (200 proof),mobile phase B was HPLC grade heptane with 0.12% diethylamine added. Thecolumn used for the chromatography was a Daicel IA, 20 × 250 mm column(5 μm particles). Detection methods were evaporative light scattering(ELSD) detection as well as optical rotation. 5 Isocratic 50% A for 20min (20 mL/min flow rate). Mobile phase A was EtOH (200 proof), mobilephase B was HPLC grade heptane with 0.1% diethylamine added. The columnused for the chromatography was a Daicel IA, 20 × 250 mm column (5 μmparticles). Detection methods were evaporative light scattering (ELSD)detection as well as optical rotation. 6 Isocratic 25% A for 18 min (20mL/min flow rate). Mobile phase A was a 50:50 mixture of HPLC grade MeOHand EtOH (200 proof), mobile phase B was HPLC grade heptane with 0.1%diethylamine added. The column used for the chromatography was a DaicelIA, 20 × 250 mm column (5 μm particles). Detection methods wereevaporative light scattering (ELSD) detection as well as opticalrotation. 7 Isocratic 30% A for 18 min (20 mL/min flow rate). Mobilephase A was a 50:50 mixture of HPLC grade MeOH and EtOH (200 proof),mobile phase B was HPLC grade heptane with 0.1% diethylamine added. Thecolumn used for the chromatography was a Daicel IA, 20 × 250 mm column(5 μm particles). Detection methods were evaporative light scattering(ELSD) detection as well as optical rotation. 8 The gradient was 15-54%A in 16 min then step to 90% A in 0.5 min, with a hold at 90% for 4.3min (20 mL/min flow rate). Mobile phase A was a 50:50 mixture of HPLCgrade MeOH and EtOH (200 proof), mobile phase B was HPLC grade heptanewith 0.1% diethylamine added. The column used for the chromatography wasa Daicel IA, 20 × 250 mm column (5 μm particles). Detection methods wereevaporative light scattering (ELSD) detection as well as opticalrotation. 9 The gradient was 10-70% A in 16 min then re-equilibrated at10% A for 9 min (20 mL/min flow rate). Mobile phase A was EtOH (200proof), mobile phase B was HPLC grade heptane with 0.1% diethylamineadded. The column used for the chromatography was a Daicel IA, 20 × 250mm column (5 μm particles). Detection methods were UV, λ = 315 nm. 10The gradient was 10-50% A in 19 min with a hold at 50% for 2 min (20mL/min flow rate). Mobile phase A was EtOH (200 proof), mobile phase Bwas HPLC grade heptane with 0.1% diethylamine added. The column used forthe chromatography was a Daicel IA, 20 × 250 mm column (5 μm particles).Detection methods were evaporative light scattering (ELSD) detection aswell as optical rotation. 11 Isocratic 60% A for 20 min (20 mL/min flowrate). Mobile phase A was EtOH (200 proof), mobile phase B was HPLCgrade heptane with 0.1% diethylamine added. The column used for thechromatography was a Daicel IA, 20 × 250 mm column (5 μm particles).Detection methods were UV, λ = 300 nm. 12 Isocratic 30% A for 25 min (20mL/min flow rate). Mobile phase A was HPLC grade IPA, mobile phase B wasHPLC grade heptane with 0.1% diethylamine added. The column used for thechromatography was a Daicel IA, 20 × 250 mm column (5 μm particles).Detection methods were evaporative light scattering (ELSD) detection aswell as optical rotation. 13 Isocratic 20% A for 20 min (20 mL/min flowrate). Mobile phase A was HPLC grade IPA, mobile phase B was HPLC gradeheptane with 0.1% diethylamine added. The column used for thechromatography was a Daicel IA, 20 × 250 mm column (5 μm particles).Detection methods were evaporative light scattering (ELSD) detection aswell as optical rotation. 14 Isocratic 100% EtOH (200 proof) for 20 min(13 mL/min flow rate). The column used for the chromatography was aDaicel IC, 20 × 250 mm column (5 μm particles). Detection methods wereevaporative light scattering (ELSD) detection as well as opticalrotation. 15 Isocratic 50% A for 20 min (20 mL/min flow rate). Mobilephase A was HPLC grade IPA, mobile phase B was HPLC grade heptane with0.1% diethylamine added. The column used for the chromatography was aDaicel IA, 20 × 250 mm column (5 μm particles). Detection methods wereevaporative light scattering (ELSD) detection as well as opticalrotation. 16 Isocratic 30% A for 18 min (20 mL/min flow rate). Mobilephase A was a 50:50 mixture of HPLC grade MeOH and EtOH (200 proof),mobile phase B was HPLC grade heptane with 0.1% diethylamine added. Thecolumn used for the chromatography was a Daicel IA, 20 × 250 mm column(5 μm particles). Detection methods were evaporative light scattering(ELSD) detection as well as optical rotation. 17 The gradient was 10-50%A in 19 min with a hold at 50% for 2 min then re- equilibrated at 10% Afor 11 min (20 mL/min flow rate). Mobile phase A was EtOH (200 proof),mobile phase B was HPLC grade heptane with 0.1% diethylamine added. Thecolumn used for the chromatography was a Daicel IC, 20 × 250 mm column(5 μm particles). Detection methods were evaporative light scattering(ELSD) detection as well as optical rotation. 18 The gradient was 10-50%A in 19 min with a hold at 50% for 1.5 min (20 mL/min flow rate). Mobilephase A was HPLC grade IPA, mobile phase B was HPLC grade heptane with0.1% diethylamine added. The column used for the chromatography was aDaicel IA, 20 × 250 mm column (5 μm particles). Detection methods wereevaporative light scattering (ELSD) detection, and/or UV (variablewavelength) as well as optical rotation. 19 The gradient was 10-50% A in19 min then re-equilibrated at 10% A for 6 min (20 mL/min flow rate).Mobile phase A was HPLC grade IPA, mobile phase B was HPLC grade heptanewith 0.1% diethylamine added. The column used for the chromatography wasa Daicel IC, 20 × 250 mm column (5 μm particles). Detection methods wereevaporative light scattering (ELSD) detection as well as opticalrotation. 20 Isocratic 40% A for 16 min (20 mL/min flow rate). Mobilephase A was HPLC grade IPA, mobile phase B was HPLC grade heptane with0.1% diethylamine added. The column used for the chromatography was aDaicel IA, 20 × 250 mm column (5 μm particles). Detection methods wereevaporative light scattering (ELSD) detection as well as opticalrotation. 21 Isocratic 40% A for 15-25 min (20 mL/min flow rate). Mobilephase A was EtOH (200 proof), mobile phase B was HPLC grade heptane with0.1% diethylamine added. The column used for the chromatography was aDaicel IA, 20 × 250 mm column (5 μm particles). Detection methods wereevaporative light scattering (ELSD) detection, and/or UV (variablewavelength) as well as optical rotation. 22 The gradient was 10-40% A in19 min (20 mL/min flow rate). Mobile phase A was EtOH (200 proof),mobile phase B was HPLC grade heptane with 0.1% diethylamine added. Thecolumn used for the chromatography was a Daicel IB, 20 × 250 mm column(5 μm particles). Detection methods were evaporative light scattering(ELSD) detection as well as optical rotation. 23 The gradient was 15-70%A in 19 min (20 mL/min flow rate). Mobile phase A was EtOH (200 proof),mobile phase B was HPLC grade heptane with 0.1% diethylamine added. Thecolumn used for the chromatography was a Daicel IA, 20 × 250 mm column(5 μm particles). Detection methods were evaporative light scattering(ELSD) detection as well as optical rotation. 24 Isocratic 15% A for 14min (20 mL/min flow rate). Mobile phase A was EtOH (200 proof), mobilephase B was HPLC grade heptane with 0.12% diethylamine added. The columnused for the chromatography was a Daicel IC, 20 × 250 mm column (5 μmparticles). Detection methods were evaporative light scattering (ELSD)detection as well as optical rotation. 25 Isocratic 30% A for 10 min (20mL/min flow rate). Mobile phase A was HPLC grade IPA, mobile phase B wasHPLC grade heptane with 0.1% diethylamine added. The column used for thechromatography was a Daicel IB, 20 × 250 mm column (5 μm particles).Detection methods were evaporative light scattering (ELSD) detection aswell as optical rotation. 26 Isocratic 40% A for 5 min then gradient 40to 95% A in 2 min, with a hold at 95% for 11 min (20 mL/min flow rate).Mobile phase A was a 50:50 mixture of HPLC grade MeOH and EtOH (200proof), mobile phase B was HPLC grade heptane with 0.1% diethylamineadded. The column used for the chromatography was a Daicel IA, 20 × 250mm column (5 μm particles). Detection methods were evaporative lightscattering (ELSD) detection as well as optical rotation. 27 The gradientwas 10-50% A in 19 min (20 mL/min flow rate). Mobile phase A was EtOH(200 proof), mobile phase B was HPLC grade heptane with 0.1%diethylamine added. The column used for the chromatography was a DaicelIB, 20 × 250 mm column (5 μm particles). Detection methods wereevaporative light scattering (ELSD) detection as well as opticalrotation. 28 Isocratic 15% A for 35 min (20 mL/min flow rate). Mobilephase A was EtOH (200 proof), mobile phase B was HPLC grade heptane with0.12% diethylamine added. The column used for the chromatography was aDaicel IA, 20 × 250 mm column (5 μm particles). Detection methods wereevaporative light scattering (ELSD) detection as well as opticalrotation. 29 The gradient was 10-50% A in 19 min with a hold at 50% for3 min then re- equilibrate at 10% A for 13 min (1 mL/min flow rate).Mobile phase A was IPA, mobile phase B was HPLC grade heptane with 0.1%diethylamine added. The column used for the chromatography was a DaicelIC, 4.6 × 250 mm column (5 μm particles). Detection methods wereevaporative light scattering (ELSD) detection as well as opticalrotation. 30 Isocratic 20% A for 20 min (1 mL/min flow rate). Mobilephase A was IPA, mobile phase B was HPLC grade heptane with 0.1%diethylamine added. The column used for the chromatography was a DaicelIC, 4.6 × 250 mm column (5 μm particles). Detection methods were UV, λ =230 nm as well as positive electrospray ionization. 31 Isocratic 20% Afor 10 min (20 mL/min flow rate). Mobile phase A was ethanol (200proof), mobile phase B was HPLC grade heptane with 0.12% diethylamineadded. The column used for the chromatography was a Daicel IA, 20 × 250mm column (5 μm particles). Detection methods were evaporative lightscattering (ELSD) detection as well as optical rotation. 32 The gradientwas 10-70% A in 19 min then re-equilibrate at 10% A for 11 min (20mL/min flow rate). Mobile phase A was ethanol (200 proof), mobile phaseB was HPLC grade heptane with 0.1% diethylamine added. The column usedfor the chromatography was a Daicel IA, 20 × 250 mm column (5 μmparticles). Detection methods were ELSD and optical rotation. 33Isocratic 30% A for 20-30 min (20 mL/min flow rate). Mobile phase A wasethanol (200 proof), mobile phase B was HPLC grade heptane with 0.12%diethylamine added. The column used for the chromatography was a DaicelIA, 20 × 250 mm column (5 μm particles). Detection methods wereevaporative light scattering (ELSD) detection, and/or UV (variablewavelength) as well as optical rotation. 34 Isocratic 40% A for 10-30min (20 mL/min flow rate). Mobile phase A was ethanol (200 proof),mobile phase B was HPLC grade heptane with 0.12% diethylamine added. Thecolumn used for the chromatography was a Daicel IC, 20 × 250 mm column(5 μm particles). Detection methods were evaporative light scattering(ELSD) detection as well as optical rotation. 35 Isocratic 15% A for22.5 min then step to 60% A and hold for 5 min (20 mL/min flow rate).Mobile phase A was HPLC grade IPA, mobile phase B was HPLC grade heptanewith 0.12% diethylamine added. The column used for the chromatographywas a Daicel IA, 20 × 250 mm column (5 μm particles). Detection methodwas UV, λ = 325 nm 36 Isocratic 40% A for 20 min (20 mL/min flow rate).Mobile phase A was a 50:50 mixture of HPLC grade MeOH and EtOH (200proof), mobile phase B was HPLC grade heptane with 0.1% diethylamineadded. The column used for the chromatography was a Daicel IA, 20 × 250mm column (5 μm particles). Detection methods were evaporative lightscattering (ELSD) detection as well as optical rotation. 37 The gradientwas 10-70% A in 19 min (20 mL/min flow rate). Mobile phase A was EtOH(200 proof), mobile phase B was HPLC grade heptane with 0.1%diethylamine added. The column used for the chromatography was a DaicelIC, 20 × 250 mm column (5 μm particles). Detection methods wereevaporative light scattering (ELSD) detection as well as opticalrotation. 38 Isocratic 35% A for 25 min (20 mL/min flow rate). Mobilephase A was HPLC grade IPA, mobile phase B was HPLC grade heptane with0.1% diethylamine added. The column used for the chromatography was aDaicel IC, 20 × 250 mm column (5 μm particles). Detection methods wereevaporative light scattering (ELSD) detection as well as opticalrotation. 39 Isocratic 70% A for 7 min then gradient 70-95% A in 3 minand hold at 95% A for 12 min (20 mL/min flow rate). Mobile phase A wasEtOH (200 proof), mobile phase B was HPLC grade heptane with 0.12%diethylamine added. The column used for the chromatography was a DaicelIA, 20 × 250 mm column (5 μm particles). Detection methods wereevaporative light scattering (ELSD) detection, and/or UV (variablewavelength) as well as optical rotation. 40 Isocratic 25% A for 25 min(20 mL/min flow rate). Mobile phase A was HPLC grade IPA, mobile phase Bwas HPLC grade heptane with 0.12% diethylamine added. The column usedfor the chromatography was a Daicel IA, 20 × 250 mm column (5 μmparticles). Detection method was UV, λ = 325 nm 41 Isocratic 10% A for25 min (20 mL/min flow rate). Mobile phase A was EtOH (200 proof),mobile phase B was HPLC grade heptane with 0.12% diethylamine added. Thecolumn used for the chromatography was a Daicel IA, 20 × 250 mm column(5 μm particles). Detection method was UV, λ = 320 nm 42 Isocratic 20% Afor 20 min (20 mL/min flow rate). Mobile phase A was EtOH (200 proof),mobile phase B was HPLC grade heptane with 0.1% diethylamine added. Thecolumn used for the chromatography was a Daicel IA, 20 × 250 mm column(5 μm particles). Detection methods were evaporative light scattering(ELSD) detection as well as optical rotation. 43 Isocratic 15% A for 30min (20 mL/min flow rate). Mobile phase A was EtOH (200 proof), mobilephase B was HPLC grade heptane with 0.1% diethylamine added. The columnused for the chromatography was a Daicel IB, 20 × 250 mm column (5 μmparticles). Detection methods were evaporative light scattering (ELSD)detection as well as optical rotation. 44 Isocratic 25% A for 25 min (20mL/min flow rate). Mobile phase A was EtOH (200 proof), mobile phase Bwas HPLC grade heptane with 0.12% diethylamine added. The column usedfor the chromatography was a Daicel IA, 20 × 250 mm column (5 μmparticles). Detection methods were evaporative light scattering (ELSD)detection as well as optical rotation. 45 The gradient was 10-60% A in20 min (20 mL/min flow rate). Mobile phase A was EtOH (200 proof),mobile phase B was HPLC grade heptane with 0.1% diethylamine added. Thecolumn used for the chromatography was a Daicel IC, 20 × 250 mm column(5 μm particles). Detection methods were evaporative light scattering(ELSD) detection, and/or UV (variable wavelength) as well as opticalrotation. 46 The gradient was 10-50% A in 13 min (20 mL/min flow rate).Mobile phase A was EtOH (200 proof), mobile phase B was HPLC gradeheptane with 0.1% diethylamine added. The column used for thechromatography was a Daicel IA, 20 × 250 mm column (5 μm particles).Detection methods were evaporative light scattering (ELSD) detection,and/or UV (variable wavelength) as well as optical rotation. 47 Thegradient was 10-50% A in 17 min (20 mL/min flow rate). Mobile phase Awas EtOH (200 proof), mobile phase B was HPLC grade heptane with 0.1%diethylamine added. The column used for the chromatography was a DaicelIA, 20 × 250 mm column (5 μm particles). Detection methods wereevaporative light scattering (ELSD) detection, and/or UV (variablewavelength) as well as optical rotation. 48 The gradient was 15-60% A in17 min (20 mL/min flow rate). Mobile phase A was a 50:50 mixture of HPLCgrade MeOH and EtOH (200 proof), mobile phase B was HPLC grade heptanewith 0.1% diethylamine added. The column used for the chromatography wasa Daicel IA, 20 × 250 mm column (5 μm particles). Detection methods wereevaporative light scattering (ELSD) detection, and/or UV (variablewavelength) as well as optical rotation. 49 Isocratic 25% A for 17 minthen step to 60% A and hold for 10 min (20 mL/min flow rate). Mobilephase A was HPLC grade IPA, mobile phase B was HPLC grade heptane with0.12% diethylamine added. The column used for the chromatography was aDaicel IC, 20 × 250 mm column (5 μm particles). Detection method was UV,λ = 340 nm 50 Isocratic 20% A for 20 min (20 mL/min flow rate). Mobilephase A was EtOH (200 proof), mobile phase B was HPLC grade heptane with0.1% diethylamine added. The column used for the chromatography was aDaicel IB, 20 × 250 mm column (5 μm particles). Detection methods wereevaporative light scattering (ELSD) detection, and/or UV (variablewavelength) as well as optical rotation. 51 Isocratic 10% A for 60 min(20 mL/min flow rate). Mobile phase A was a 50:50 mixture of HPLC gradeMeOH and EtOH (200 proof), mobile phase B was HPLC grade heptane with0.12% diethylamine added. The column used for the chromatography was aDaicel IA, 20 × 250 mm column (5 μm particles). Detection methods wereevaporative light scattering (ELSD) detection as well as opticalrotation. 52 Isocratic 50% A for 20 min (20 mL/min flow rate). Mobilephase A was a 50:50 mixture of HPLC grade MeOH and EtOH (200 proof),mobile phase B was HPLC grade heptane with 0.12% diethylamine added. Thecolumn used for the chromatography was a Daicel IC, 20 × 250 mm column(5 μm particles). Detection methods were evaporative light scattering(ELSD) detection as well as optical rotation. 53 The gradient was 30-70%A in 18 min with a hold at 70% for 4 min then re- equilibrate at 30% Afor 13 min (20 mL/min flow rate). Mobile phase A was IPA, mobile phase Bwas HPLC grade heptane with 0.12% diethylamine added. The column usedfor the chromatography was a Daicel IC, 20 × 250 mm column (5 μmparticles). Detection methods were evaporative light scattering (ELSD)detection as well as optical rotation. 54 Isocratic 30% A for 30 min (20mL/min flow rate). Mobile phase A was ethanol (200 proof), mobile phaseB was HPLC grade heptane with 0.12% diethylamine added. The column usedfor the chromatography was a Daicel IC, 20 × 250 mm column (5 μmparticles). Detection methods were evaporative light scattering (ELSD)detection, and/or UV (variable wavelength) as well as optical rotation.55 Isocratic 30% A for 30 min (20 mL/min flow rate). Mobile phase A wasethanol (200 proof), mobile phase B was HPLC grade heptane with 0.12%diethylamine added. The column used for the chromatography was a (R,R)Whelk-O1, 21 × 250 mm column (5 μm particles). Detection methods wereevaporative light scattering (ELSD) detection, and/or UV (variablewavelength) as well as optical rotation. 56 Isocratic 35% A for 30 min(20 mL/min flow rate). Mobile phase A was ethanol (200 proof), mobilephase B was HPLC grade heptane with 0.12% diethylamine added. The columnused for the chromatography was a Daicel IC, 20 × 250 mm column (5 μmparticles). Detection methods were evaporative light scattering (ELSD)detection, and/or UV (variable wavelength) as well as optical rotation.57 Isocratic 30% A for 30 min (20 mL/min flow rate). Mobile phase A wasa 50:50 mixture of HPLC grade MeOH and EtOH (200 proof), mobile phase Bwas HPLC grade heptane with 0.12% diethylamine added. The column usedfor the chromatography was a Daicel IC, 20 × 250 mm column (5 μmparticles). Detection methods were evaporative light scattering (ELSD)detection, and/or UV (variable wavelength) as well as optical rotation.58 Isocratic 15% A for 11 min then step to 50% A in 0.5 min and hold for4.5 min (20 mL/min flow rate). Mobile phase A was HPLC grade ethanol(200 proof), mobile phase B was HPLC grade heptane with 0.12%diethylamine added. The column used for the chromatography was a DaicelIA, 20 × 250 mm column (5 μm particles). Detection methods wereevaporative light scattering (ELSD) detection, and/or UV (variablewavelength) as well as optical rotation. 59 The gradient was 10-95% A in17 min with a hold at 95% for 2 min (20 mL/min flow rate). Mobile phaseA was EtOH (200 proof), mobile phase B was HPLC grade heptane with 0.12%diethylamine added. The column used for the chromatography was a DaicelIA, 20 × 250 mm column (5 μm particles). Detection methods wereevaporative light scattering (ELSD) detection, and/or UV (variablewavelength) as well as optical rotation. 60 Isocratic 20% A for 10 minthen step to 60% A in 0.5 min and hold at 60% for 5.5 min (20 mL/minflow rate). Mobile phase A was HPLC grade IPA, mobile phase B was HPLCgrade heptane with 0.12% diethylamine added. The column used for thechromatography was a Daicel IA, 20 × 250 mm column (5 μm particles).Detection methods were evaporative light scattering (ELSD) detection,and/or UV (variable wavelength) as well as optical rotation. 61 Thegradient was 10-20% A in 28 min, hold at 20% for 2 min then 20-70% A in5 min (20 mL/min flow rate). Mobile phase A was EtOH (200 proof), mobilephase B was HPLC grade heptane with 0.12% diethylamine added. The columnused for the chromatography was a Daicel IC, 20 × 250 mm column (5 μmparticles). Detection methods were evaporative light scattering (ELSD)detection, and/or UV (variable wavelength) as well as optical rotation.62 Isocratic 22% A for 30 min (20 mL/min flow rate). Mobile phase A wasEtOH (200 proof), mobile phase B was HPLC grade heptane with 0.12%diethylamine added. The column used for the chromatography was a DaicelIB, 20 × 250 mm column (5 μm particles). Detection methods wereevaporative light scattering (ELSD) detection, and/or UV (variablewavelength) as well as optical rotation. 63 Isocratic 25% A for 30 min(20 mL/min flow rate). Mobile phase A was EtOH (200 proof), mobile phaseB was HPLC grade heptane with 0.12% diethylamine added. The column usedfor the chromatography was a Daicel IB, 20 × 250 mm column (5 μmparticles). Detection methods were evaporative light scattering (ELSD)detection, and/or UV (variable wavelength) as well as optical rotation.64 Isocratic 65% A for 30 min (20 mL/min flow rate). Mobile phase A wasethanol (200 proof), mobile phase B was HPLC grade heptane with 0.12%diethylamine added. The column used for the chromatography was a (R,R)Whelk-O1, 21 × 250 mm column (5 μm particles). Detection methods wereevaporative light scattering (ELSD) detection, and/or UV (variablewavelength) as well as optical rotation. 65 Isocratic 65% A for 6 minthen step to 90% A in 0.5 min and hold at 90% for 6.5 min (20 mL/minflow rate). Mobile phase A was ethanol (200 proof), mobile phase B wasHPLC grade heptane with 0.12% diethylamine added. The column used forthe chromatography was a (R,R) Whelk-O1, 21 × 250 mm column (5 μmparticles). Detection methods were evaporative light scattering (ELSD)detection, and/or UV (variable wavelength) as well as optical rotation.66 Isocratic 30% A for 30 min (20 mL/min flow rate). Mobile phase A wasHPLC grade IPA, mobile phase B was HPLC grade heptane with 0.12%diethylamine added. The column used for the chromatography was a DaicelIC, 20 × 250 mm column (5 μm particles). Detection methods wereevaporative light scattering (ELSD) detection, and/or UV (variablewavelength) as well as optical rotation. 67 Isocratic 55% A for 8 minthen step to 90% A in 1 min and hold at 90 for 7 min (20 mL/min flowrate). Mobile phase A was EtOH (200 proof), mobile phase B was HPLCgrade heptane with 0.12% diethylamine added. The column used for thechromatography was a Daicel IC, 20 × 250 mm column (5 μm particles).Detection methods were evaporative light scattering (ELSD) detection,and/or UV (variable wavelength) as well as optical rotation. 68 Thegradient was 60-90% A in 4 min with a hold at 90% for 6 min (20 mL/minflow rate). Mobile phase A was EtOH (200 proof), mobile phase B was HPLCgrade heptane with 0.12% diethylamine added. The column used for thechromatography was a Daicel IA, 20 × 250 mm column (5 μm particles).Detection methods were evaporative light scattering (ELSD) detection,and/or UV (variable wavelength) as well as optical rotation. 69Isocratic 20% A for 12 min then step to 50% A in 0.5 min and hold at 50%for 3.5 min (20 mL/min flow rate). Mobile phase A was EtOH (200 proof),mobile phase B was HPLC grade heptane with 0.12% diethylamine added. Thecolumn used for the chromatography was a Daicel IA, 20 × 250 mm column(5 μm particles). Detection methods were evaporative light scattering(ELSD) detection, and/or UV (variable wavelength) as well as opticalrotation. 70 The gradient was 20-50% B over 10 min (0.6 mL/min flowrate). Mobile phase A was 10 mM KH₂PO₄ buffer (pH = 6.9) and mobilephase B was HPLC grade MeCN. The column used for the chromatography wasa 4.6 × 150 mm Chiralpak AS-RH, Diacel col. Detection method was UV. 71The gradient was 15-85% A in 37 min with a hold at 85% A for 0.5 min (20mL/min flow rate). Mobile phase A was HPLC grade IPA, mobile phase B wasHPLC grade heptane with 0.12% diethylamine added. The column used forthe chromatography was a Daicel IC, 20 × 250 mm column (5 μm particles).Detection methods were evaporative light scattering (ELSD) detection,and/or UV (variable wavelength) as well as optical rotation.

Purification Methods

For the general procedures, the intermediates and final compounds may bepurified by any technique or combination of techniques known to oneskilled in the art. Some examples that are not limiting include flashchromatography with a solid phase (e.g. silica gel, alumina, etc.) and asolvent (or combination of solvents) that elutes the desired compounds(e.g. heptane, EtOAc, DCM, MeOH, MeCN, water, etc.); preparatory TLCwith a solid phase (e.g. silica gel, alumina etc.) and a solvent (orcombination of solvents) that elutes the desired compounds (e.g.heptane, EtOAc, DCM, MeOH, MeCN, water, etc.); reverse phase HPLC (seeTable 1 for some non-limiting conditions); recrystallization from anappropriate solvent or combination of solvents (e.g. MeOH, EtOH, IPA,EtOAc, toluene, etc.) or combination of solvents (e.g. EtOAc/heptane,EtOAc/MeOH, etc.); chiral LC with a solid phase and an appropriatesolvent (see Table 2 for some non-limiting conditions) to elute thedesired compound; chiral SFC with a solid phase and CO₂ with anappropriate modifier (e.g. MeOH, EtOH, IPA with or without additionalmodifier such as diethylamine, TFA, etc.); precipitation from acombination of solvents (e.g. DMF/water, DMSO/DCM, EtOAc/heptane, etc.);trituration with an appropriate solvent (e.g. EtOAc, DCM, MeCN, MeOH,EtOH, IPA, n-IPA, etc.); extractions by dissolving a compound in aliquid and washing with an appropriately immiscible liquid (e.g.DCM/water, EtOAc/water, DCM/saturated aqueous NaHCO₃, EtOAc/saturatedaqueous NaHCO₃, DCM/10% aqueous HCl, EtOAc/10% aqueous HCl, etc.);distillation (e.g. simple, fractional, Kugelrohr, etc.); gaschromatography using an appropriate temperature, carrier gas and flowrate; sublimation at an appropriate temperature and pressure; filtrationthrough a media (e.g. Florosil®, alumina, Celite®, silica gel, etc.)with a solvent (e.g. heptane, hexanes, EtOAc, DCM, MeOH, etc.) orcombination of solvents; salt formation with solid support (resin based,e.g. ion exchange) or without. Compounds of interest may be isolated asa salt without the use of a specific salt formation purification method.For example, on occasions where purification is accomplished withreverse phase HPLC with an aqueous TFA buffer, the TFA salt may beisolated. Some descriptions of these techniques can be found in thefollowing references: Gordon, A. J. and Ford, R. A. “The Chemist'sCompanion”, 1972; Palleros, D. R. “Experimental Organic Chemistry”,2000; Still, W. C., Kahn and M. Mitra, A. J. Org. Chem. 1978, 43, 2923;Yan, B. “Analysis and Purification Methods in Combinatorial Chemistry”,2003; Harwood, L. M., Moody, C. J. and Percy, J. M. “ExperimentalOrganic Chemistry: Standard and Microscale, 2^(nd) Edition”, 1999;Stichlmair, J. G. and Fair, J. R. “Distillation; Principles andPractices”, 1998; Beesley, T. E. and Scott, R. P. W. “ChiralChromatography”, 1999; Landgrebe, J. A. “Theory and Practice in theOrganic Laboratory, 4^(th) Ed.”, 1993; Skoog, D. A. and Leary, J. J.“Principles of Instrumental Analysis, 4^(th) Ed.”, 1992; G. Subramanian,“Chiral Separation Techniques, 3^(rd) Edition”, 2007; Y. Kazakevich, R.Lobrutto, “HPLC for Pharmaceutical Scientists”, 2007.

PREPARATIONS AND EXAMPLES

The general synthetic methods used in each General Procedure follow andinclude an illustration of a compound that was synthesized using thedesignated General Procedure. None of the specific conditions andreagents noted herein are to be construed as limiting the scope of theinvention and are provided for illustrative purposes only. All startingmaterials are commercially available from Sigma-Aldrich (including Flukaand Discovery CPR) unless otherwise noted after the chemical name.Reagent/reactant names given are as named on the commercial bottle or asgenerated by IUPAC conventions, CambridgeSoft® ChemDraw Ultra 9.0.7,CambridgeSoft® Chemistry E-Notebook 9.0.127, or AutoNom 2000. Compoundsdesignated as salts (e.g. hydrochloride, acetate) may contain more thanone molar equivalent of the salt. Compounds of the invention where theabsolute stereochemistry has been determined by the use of acommercially available enantiomerically pure starting material or astereochemically defined intermediate, or by X-ray diffraction aredenoted by an asterisk after the example number.

Preparation #1 cis-3-(4-cyanobenzyloxy)cyclobutanecarboxylic acid

Step A cis-ethyl 3-hydroxycyclobutanecarboxylate

A solution of ethyl 3-oxocyclobutanecarboxylate (2.90 g, 20.4 mmol,Parkway) in EtOH (30 mL) at ambient temperature was treated with NaBH₄(0.77 g, 20 mmol). The reaction was stirred for about 1 h and then 2 Naqueous HCl was added to adjust the pH to about 2. The reaction wasconcd in vacuo. The reaction was partitioned with DCM (50 mL) and brine(50 mL). The organic layer was separated, dried over anhydrous Na₂SO₄,filtered then concd in vacuo. The resulting residue was purified onsilica gel (80 g) using 20-40% EtOAc in DCM to give cis-ethyl3-hydroxycyclobutanecarboxylate (2.75 g, 66%) as a clear oil: ¹H NMR(DMSO-d₆) δ 5.17 (d, 1H), 4.09-3.99 (m, 2H), 3.99-3.90 (m, 1H),2.57-2.47 (m, 1H), 2.42-2.29 (m, 2H), 1.98-1.89 (m, 2H), 1.17 (m, 3H).

Step B: cis-ethyl 3-(4-cyanobenzyloxy)cyclobutanecarboxylate

To a solution of cis-ethyl 3-hydroxycyclobutanecarboxylate (0.17 g, 1.2mmol) in DMF (4 mL) was added K₂CO₃ (0.24 g, 1.8 mmol) followed by4-(bromomethyl)benzonitrile (0.28 g, 1.4 mmol). The reaction was stirredat about 25° C. for about 16 h. The reaction was partitioned betweenEtOAc (50 mL) and brine (50 mL). The layers were separated and theorganic layer was washed with additional brine (50 mL). The organiclayer was then dried over anhydrous Na₂SO₄, filtered, and concd in vacuoto give cis-ethyl 3-(4-cyanobenzyloxy)-cyclobutanecarboxylate (0.29 g,95%) as an oil: ¹H NMR (DMSO-d₆) δ 7.82 (d, J=8.5 Hz, 2H), 7.63 (d,J=8.4 Hz, 2H), 4.75 (s, 2H), 4.02 (q, J=7.1 Hz, 2H), 3.93 (m, 1H),2.58-2.45 (m, 1H), 2.41-2.28 (m, 2H), 1.98-1.85 (m, 2H), 1.20-1.08 (t,J=7.1 Hz, 3H).

Step C: cis-3-(4-cyanobenzyloxy)cyclobutanecarboxylic acid

To a solution of cis-ethyl 3-(4-cyanobenzyloxy)cyclobutanecarboxylate(0.44 g, 1.70 mmol) in 1,4-dioxane (10 mL) was added aqueous NaOH (1 N,2.0 mL). The reaction was stirred at about 25° C. for about 16 h. Thereaction was partitioned between 10% aqueous AcOH (20 mL) and EtOAc (25mL). The layers were separated and the aqueous layer was extracted withadditional EtOAc (25 mL). The combined organic extracts were washed withbrine (20 mL), dried over anhydrous Na₂SO₄, filtered then concd in vacuoto give cis-3-(4-cyanobenzyloxy)-cyclobutanecarboxylic acid (0.24 g,60%): LC/MS (Table 1, Method b) R_(t)=1.67 min; MS m/z: 232 (M+H)⁺.

Preparation #2*(1S,3R)-1-[3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-isothiazolidin-2-yl-1,1-dioxide]cyclopentane

Step A3-chloro-N-((1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)propane-1-sulfonamide

To a suspension of(1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanaminehydrochloride (0.05 g, 0.11 mmol, prepared using E from Preparation #B.1and HCl) and TEA (0.03 mL, 0.21 mmol) in DCM (5 mL) at about 0° C. wasadded 3-chloropropane-1-sulfonyl chloride (0.02 g, 0.11 mmol) dropwise.The reaction mixture was stirred at about 0° C. for about 1.5 h. Thereaction mixture was diluted with 5% aqueous citric acid (10 mL), andthe layers were separated. The organic layer was washed with saturatedaqueous NaHCO₃ (10 mL), water (10 mL), brine (10 mL), dried overanhydrous MgSO₄, filtered, and concd under reduced pressure to give3-chloro-N-((1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)propane-1-sulfonamide(0.052 g, 91%) as a brown residue: LC/MS (Table 1, Method a) R_(t)=2.18min; MS m/z: 537 (M+H)⁺.

Step B:(1S,3R)-1-[3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-isothiazolidin-2-yl-1,1-dioxide]cyclopentane

To a solution of3-chloro-N-((1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)propane-1-sulfonamide(0.11 g, 0.21 mmol) in DMF (5 mL) was added1,8-diazabicyclo[5.4.0]undec-7-ene (0.04 mL, 0.27 mmol crude). Thereaction mixture was stirred at ambient temperature for about 16 h. Thesolvent was removed under reduced pressure to give(1S,3R)-1-[3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-isothiazolidin-2-yl-1,1-dioxide]cyclopentane(0.106 g, 99%): LC/MS (Table 1, Method a) R_(t)=2.04 min; MS m/z: 501(M+H)⁺.

Preparation #3*1-((1R,3S)-3-(1H-pyrrol-1-yl)cyclopentyl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine

A solution of 2,5-dimethoxytetrahydrofuran (0.14 g, 1.1 mmol) in water(3 mL) was heated at about 100° C. for about 1.5 h. The solution wascooled to ambient temperature. A suspension of(1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclo-pentanaminehydro-chloride (0.10 g, 0.21 mmol, prepared using E from Preparation#B.1 and HCl) and NaOAc (0.05 g, 0.61 mmol) in DCM (5 mL) was added tothe aqueous solution. The reaction mixture was stirred at ambienttemperature for about 1 h followed by addition of additional2,5-dimethoxytetrahydrofuran (0.14 g, 1.1 mmol). The reaction mixturewas heated to about 40° C. for about 15 h. Additional2,5-dimethoxytetrahydrofuran (0.14 g, 1.1 mmol) was added and thereaction mixture was stirred at about 40° C. for about 8 h then at about35° C. for about 48 h. The reaction was diluted with DCM (10 mL) andwater (10 mL). The layers were separated and the organic layer waswashed with water (2×10 mL) and brine (10 mL), dried over anhydrousMgSO₄, filtered, and the solvent was removed under reduced pressure togive1-((1R,35)-3-(1H-pyrrol-1-yl)cyclopentyl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine(0.095 g, 99%) as a yellow residue LC/MS (Table 1, Method a) R_(t)=2.42min; MS m/z: 447 (M+H)⁺.

Preparation #4*1-((1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-1H-pyrrole-3-carbonitrile

Step A1-((1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-1H-pyrrole-3-carbaldehyde

To a suspension of(1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanaminehydrochloride (0.175 g, 0.373 mmol, prepared using E from Preparation#B.1 and HCl) and NaOAc (0.100 g, 1.22 mmol) in DCM (3 mL) and water (2mL) was added 2,5-dimethoxytetrahydrofuran-3-carbaldehyde (0.600 g, 3.37mmol). The reaction was heated to about 40° C. for about 24 h. Thereaction mixture was diluted with DCM (30 mL) and washed with water(4×20 mL). The organic layer was dried over anhydrous MgSO₄, filtered,and the solvent was removed under reduced pressure to give a brownresidue. The crude material was purified by flash chromatography onsilica gel eluting with a gradient of 20-100% EtOAc in DCM to give1-((1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-1H-pyrrole-3-carbaldehyde(0.059 g, 33%) as a yellow amorphous solid: LC/MS (Table 1, Method a)R_(t)=2.10 min; MS m/z: 475 (M+H)⁺.

Step B:1-((1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-1H-pyrrole-3-carbonitrile

To a solution of1-((1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-1H-pyrrole-3-carbaldehyde(0.050 g, 0.105 mmol) in THF (2 mL) was added iodine (0.083 g, 0.327mmol) and aqueous NH₄OH (28-30% w/v, 0.733 mL, 5.27 mmol). The reactionmixture was stirred at ambient temperature for about 24 h. The reactionmixture was diluted with saturated aqueous Na₂SO₃ (30 mL) and EtOAc (30mL). The layers were partitioned and the organic layer was dried overanhydrous MgSO₄, filtered, and the solvent was removed under reducedpressure to give1-((1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-1H-pyrrole-3-carbonitrile(0.05 g, 100%): LC/MS (Table 1, Method a) R_(t)=2.33 min; MS m/z: 472(M+H)⁺.

Preparation #53,3-difluoro-N-(4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)azetidine-1-sulfonamide

Step A 1-(1H-imidazol-1-ylsulfonyl)-3-methyl-1H-imidazol-3-iumtrifluoromethanesulfonate

To a solution of 1,1′-sulfonyldiimidazole (3.50 g, 17.7 mmol) in DCM (75mL) at about 0° C. was added methyl trifluoromethanesulfonate (1.94 mL,17.7 mmol). The reaction mixture was stirred at about 0° C. for about 1h, then warmed to ambient temperature and stirred for about 5 h. Thesolid was collected by vacuum filtration and washed with DCM (10 mL) togive 1-(1H-imidazol-1-ylsulfonyl)-3-methyl-1H-imidazol-3-iumtrifluoromethanesulfonate (6.35 g, 98%) as a white solid: LC/MS (Table1, Method a) R_(t)=0.082 min; MS m/z 213 (M+H)⁺.

Step B: 1-(3,3-difluoroazetidin-1-ylsulfonyl)-1H-imidazole

A solution of 3,3-difluoroazetidine hydrochloride (1.00 g, 7.72 mmol)and DIEA (1.5 mL, 8.6 mmol) in MeCN (5 mL) was stirred for about 5 minand then was added to a solution of1-(1H-imidazol-1-ylsulfonyl)-3-methyl-1H-imidazol-3-iumtrifluoromethanesulfonate (4.20 g, 11.6 mmol) in MeCN (10 mL) at about0° C. The reaction mixture was stirred at about 0° C. for about 1 h, andthen warmed to ambient temperature and stirred for about 16 h. Thereaction mixture was then concd under reduced pressure. The crudematerial was purified by flash chromatography on silica gel eluting witha gradient of 5-100% EtOAc in DCM to give1-((3,3-difluoroazetidin-1-ylsulfonyl)-1H-imidazole (0.95 g, 55%) as ayellow solid: LC/MS (Table 1, Method c) R_(t)=1.16 min; MS m/z 224(M+H)⁺.

Step C: 1-(3,3-difluoroazetidin-1-ylsulfonyl)-3-methyl-1H-imidazol-3-iumtrifluoromethanesulfonate

To a solution of 1-(3,3-difluoroazetidin-1-ylsulfonyl)-1H-imidazole(0.500 g, 2.24 mmol) in DCM (5 mL) at about 0° C. was added methyltrifluoromethanesulfonate (0.27 mL, 2.46 mmol) dropwise over about 3min. The reaction mixture was stirred at about 0° C. for about 2 h. Thesolid was collected by vacuum filtration, washed with DCM (10 mL), anddried under vacuum to give1-(3,3-difluoroazetidin-1-ylsulfonyl)-3-methyl-1H-imidazol-3-iumtrifluoromethanesulfonate (0.79 g, 90%) as a white solid: LC/MS (Table1, Method c) R_(t)=1.12 min; MS m/z 238 (M+H)⁺.

Step D:3,3-difluoro-N-(4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)azetidine-1-sulfonamide

To a solution of4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]-octan-1-amine(0.20 g, 0.46 mmol, Example #9, Step F) in MeCN (5 mL) was added1-(3,3-difluoroazetidin-1-ylsulfonyl)-3-methyl-1H-imidazol-3-iumtrifluoromethanesulfonate (0.19 g, 0.50 mmol). The reaction mixture washeated to about 70° C. for about 24 h. The solvent was removed underreduced pressure. The residue was partitioned between EtOAc (30 mL) andwater (10 mL). The layers were separated and the organic layer waswashed with water (10 mL) and brine (2×10 mL), dried over anhydrousMgSO₄, filtered, and the solvent was removed under reduced pressure. Thecrude material was purified by flash chromatography on silica geleluting with a gradient of 0-10% MeOH in DCM to give3,3-difluoro-N-(4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)azetidine-1-sulfonamide(0.119 g, 38%): LC/MS (Table 1, Method a) R_(t)=2.32 min; MS m/z 592(M+H)⁺.

Preparation #6 1-methylcyclopropane-1-sulfonyl chloride

Step A butyl cyclopropanesulfonate

To a solution of cyclopropanesulfonyl chloride (5.00 g, 35.6 mmol) inn-BuOH (20 mL) at −20° C., pyridine (5.75 mL, 71.1 mmol) was addeddropwise. The resulting mixture was stirred for about 16 h while warmingslowly to ambient temperature. The solvents were removed under reducedpressure and the residue was partitioned between DCM and water (50 mLeach). The organic phase was further washed with brine (40 mL), driedover anhydrous MgSO₄ and concd under reduced pressure to yield butylcyclopropanesulfonate (4.7 g, 74%) as a yellow oil. ¹H NMR (DMSO-d₆) δ4.2 (t, 2H), 2.82 (m, 1H), 1.64 (m, 2H), 1.35 (m, 2H), 1.08 (m, 2H),1.01 (m, 2H), 0.89 (t, 3H).

Step B: butyl 1-methylcyclopropane-1-sulfonate

To a solution of butyl cyclopropanesulfonate (1.5 g, 8.4 mmol) in THF (8mL) at about −78° C., n-BuLi (1.6 M in hexanes, 5.26 mL, 8.42 mmol) andiodomethane (0.684 mL, 10.9 mmol) were added simultaneously and theresulting mixture was stirred at about −78° C. for about 2 h and then atambient temperature for about 2 h. The reaction was quenched by theaddition of saturated aqueous NH₄Cl (7 mL) and the layers wereseparated. The aqueous layer was back extracted with EtOAc (15 mL) andthe combined organic extracts were dried over anhydrous MgSO₄ and concdunder reduced pressure. The residue was subjected to silica gel columnchromatography (5 to 25% EtOAc in heptane over 30 min) to yield butyl1-methylcyclopropane-1-sulfonate (0.8 g, 49%) as a colorless oil. ¹H NMR(DMSO-d₆) δ 4.17 (t, 2H), 1.62 (m, 2H), 1.43 (s, 3H), 1.35 (m, 2H), 1.22(m, 2H), 0.94 (m, 2H), 0.88 (t, 3H).

Step C: 1-methylcyclopropane-1-sulfonyl chloride

A mixture of butyl 1-methylcyclopropane-1-sulfonate (0.80 g, 4.2 mmol)and potassium thiocyanate (0.404 g, 4.16 mmol) in 1,4-dioxane/water(1:1, 10 mL) was heated at reflux for about 8 h. The reaction was cooledto ambient temperature and the solvents were concd under reducedpressure to yield crude potassium 1-methylcyclopropane-1-sulfonate whichwas suspended in thionyl chloride (7 mL). DMF (0.05 mL) was added andthe mixture was heated at reflux for about 8 h and then cooled. Thevolatiles were removed under reduced pressure and the residue wasdissolved in DCM (20 mL), washed with water (15 mL), dried overanhydrous MgSO₄ and concd under reduced pressure to yield1-methylcyclopropane-1-sulfonyl chloride (0.56 g, 86%) as a yellow oil.¹H NMR (DMSO-d₆) δ 1.82 (br s, 2H), 1.79 (s, 3H), 1.15 (m, 2H).

Preparation #7 ethyl4-(cyclopropanesulfonamido)-2-ethyl-1-fluorocyclopentanecarboxylate

A solution of ethyl4-(cyclopropanesulfonamido)-2-ethylcyclopentanecarboxylate (0.630 g,2.18 mmol, prepared using K from Preparation #Y.1 andcyclopropanesulfonyl chloride) in THF (14.5 mL) was cooled to about −78°C. and then LDA (1.8 M in THF/hexane, 3.63 mL, 6.53 mmol) was addeddropwise to the reaction mixture over about 30 min. The reaction mixturewas stirred at about −78° C. for about 50 min before a solution ofN-fluoro-N-(phenylsulfonyl)benzenesulfonamide (2.06 g, 6.53 mmol) in THF(7.3 mL) was added dropwise over about 30 min. The reaction mixture wasstirred at about −78° C. for about 1 h and then was warmed to ambienttemperature and stirred for about 16 h. Saturated aqueous NH₄Cl (100 mL)was added. The reaction mixture was partitioned with EtOAc (50 mL). Theaqueous layer was further extracted with EtOAc (2×50 mL). The combinedorganic layers were concd under reduced pressure. The residue waspurified by silica gel chromatography eluting with a gradient of 0-60%EtOAc in heptane to yield ethyl4-(cyclopropanesulfonamido)-2-ethyl-1-fluorocyclopentanecarboxylate(0.41 g, 46%) as clear oil: LC/MS (Table 1, Method b) R_(t)=2.12 min; MSm/z: 306 (M−H)⁻.

Preparation #8 (1S,2R,4R)-ethyl2-methyl-4-(phenylamino)cyclopentanecarboxylate and (1R,2S,4S)-ethyl2-methyl-4-(phenylamino)cyclopentanecarboxylate

A solution of ethyl 4-hydroxy-2-methylcyclopentanecarboxylate (1.81 g,10.5 mmol, prepared using P from Example #7, step G and NaBH₄) andpyridine (1.28 mL, 15.8 mmol) in THF (52.5 mL) was cooled to about 0° C.Methanesulfonyl chloride (0.90 mL, 12 mmol) was added dropwise. Thereaction mixture was stirred at ambient temperature for about 16 h thenpartitioned between water (50 mL) and DCM (30 mL). The layers wereseparated and the aqueous layer was extracted with DCM (2×30 mL). Thecombined organic layers were dried over anhydrous Na₂SO₄ and concd underreduced pressure to give a white solid. The resulting solid was mixedwith aniline (78.0 g, 841 mmol) and heated at about 90° C. for about 16h. The reaction mixture was concd under reduced pressure and purified bysilica gel chromatography eluting with a gradient of 20-100% EtOAc inDCM to yield (1S,2R,4R)-ethyl2-methyl-4-(phenylamino)cyclopentanecarboxylate and (1R,2S,4S)-ethyl2-methyl-4-(phenylamino)cyclo-pentanecarboxylate with 29 mol % anilineas an excipient (2.73 g, 75%) as a dark oil: LC/MS (Table 1, Method b)R_(t)=2.67 min; MS m/z: 248 (M+H)⁺.

Preparation #9 1-tert-butyl 3-ethyl4-ethyl-5,6-dihydropyridine-1,3(2H)-dicarboxylate

Step A: 1-tert-butyl 3-ethyl4-(diethoxyphosphoryloxy)-5,6-dihydropyridine-1,3(2H)-dicarboxylate

To a solution of 1-tert-butyl 3-ethyl 4-oxopiperidine-1,3-dicarboxylate(11.50 g, 42.4 mmol, ASDI) in MTBE (500 mL) at about −78° C. was addedNaHMDS (1 M in THF, 53.0 mL, 53.0 mmol). After about 1 h, diethylphosphorochloridate (7.62 mL, 53.0 mmol) was added to the reactionmixture. After about 30 min, the reaction mixture was allowed to warm toambient temperature and stirred for about 16 h. The reaction mixture waspartitioned between saturated aqueous NH₄Cl (100 mL) and EtOAc (50 mL).The layers were separated. The aqueous layer was further extracted withEtOAc (2×50 mL). The combined organic layers were dried over anhydrousNa₂SO₄, filtered, and concd under reduced pressure. The crude materialwas purified by silica gel chromatography eluting with a gradient of0-100% EtOAc in heptane to yield 1-tert-butyl 3-ethyl4-(diethoxyphosphoryloxy)-5,6-dihydropyridine-1,3(2H)-dicarboxylate(8.55 g, 49%) as a yellow oil: LC/MS (Table 1, Method b) R_(t)=2.35 min;MS m/z: 408 (M+H)⁺.

Step B: 1-tert-butyl 3-ethyl4-ethyl-5,6-dihydropyridine-1,3(2H)-dicarboxylate

To a slurry of CuI (4.21 g, 22.12 mmol) in THF (61.4 mL) at about 0° C.was added ethylmagnesium bromide (1.0 M in THF, 44.2 mL, 44.2 mmol)dropwise. After about 30 min, the reaction mixture was cooled to about−78° C. and a solution of 1-tert-butyl 3-ethyl4-(diethoxyphosphoryloxy)-5,6-dihydropyridine-1,3(2H)-dicarboxylate(7.51 g, 18.43 mmol) in THF (61 mL) was added slowly. The reactionmixture was stirred at about −78° C. for about 1 h then warmed to about0° C. The reaction mixture was stirred at about 0° C. for about 1.5 h,then warmed to ambient temperature and stirred for about 1 h. Thereaction mixture was cooled to about −78° C. and saturated aqueous NH₄Cl(100 mL) was slowly added. The reaction mixture was allowed to warm toambient temperature and stirred for about 16 h. The mixture wasextracted with Et₂O (100 mL). The aqueous layer was further extractedwith Et₂O (2×50 mL). The organic layers were combined, washed withsaturated aqueous NH₄Cl (50 mL), dried over anhydrous Na₂SO₄, filtered,concd under reduced pressure and purified by silica gel chromatographyeluting with a gradient of 0-30% EtOAc in heptane to yield 1-tert-butyl3-ethyl 4-ethyl-5,6-dihydropyridine-1,3(2H)-dicarboxylate (0.785 g, 15%)as a clear oil: ¹H NMR (CDCl₃) δ 4.23 (d, J=7.1 Hz, 2H), 4.12 (s, 2H),3.48 (t, J=5.8 Hz, 2H), 2.52 (q, J=7.5 Hz, 2H), 2.28 (t, J=5.8 Hz, 2H),1.51 (s, 9H), 1.32 (t, J=7.1 Hz, 3H), 1.09 (t, J=7.5 Hz, 3H).

Preparation #101-(1-benzylpiperidin-3-yl)-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine

Step A: tert-butyl 2-(1-benzylpiperidin-3-yl)hydrazinecarboxylate

A mixture of 1-benzylpiperidin-3-one hydrochloride (1.00 g, 4.10 mmol),tert-butyl hydrazinecarboxylate (0.596 g, 4.51 mmol), and AcOH (0.470mL, 8.21 mmol) in DCE (20 mL) was stirred at ambient temperature forabout 1 h then NaCNBH₃ (0.258 g, 4.10 mmol) was added. The reactionmixture was stirred at ambient temperature for about 16 h. The reactionmixture was quenched by the addition of saturated aqueous NaHCO₃ (50mL). The organic layer was separated, concd under reduced pressure andpurified by RP-HPLC (Table 1, Method h) to afford tert-butyl2-(1-benzylpiperidin-3-yl)hydrazinecarboxylate (1.25 g, 100%) as a clearoil: LC/MS (Table 1, Method b) R_(t)=1.66 min; MS m/z: 306 (M+H)⁺.

Step B: 1-benzyl-3-hydrazinylpiperidine hydrochloride

A solution of tert-butyl 2-(1-benzylpiperidin-3-yl)hydrazinecarboxylate(1.25 g, 4.10 mmol) in aqueous HCl (6 N, 6.83 mL, 41.0 mmol) was stirredat ambient temperature for about 8 h. The solvent was removed underreduced pressure to give crude 1-benzyl-3-hydrazinylpiperidinehydrochloride (1.45 g, 112%) as a white solid which was used withoutfurther purification: LC/MS (Table 1, Method b) R_(t)=0.66 min; MS m/z:206 (M+H)⁺.

Step C:1-(1-benzylpiperidin-3-yl)-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine

4-Chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (0.40 g, 2.21 mmol,Adesis) and 1-benzyl-3-hydrazinylpiperidine hydrochloride (1.39 g, 4.43mmol) were suspended in n-BuOH (11.1 mL). The mixture was heated atabout 90° C. for about 3 h and then heated at about 120° C. for about 5h. The reaction mixture was cooled to ambient temperature and thesolvent was removed under reduced pressure. The residue was purified bysilica gel chromatography eluting with a gradient of 0-5% MeOH in DCM toyield1-(1-benzylpiperidin-3-yl)-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine(0.105 g, 14%) as a brown oil: LC/MS (Table 1, Method b) R_(t)=1.53 min;MS m/z: 332 (M+H)⁺.

Preparation #11 cis-3-tert-butyl 1-methyl4-ethylcyclopentane-1,3-dicarboxylate

Step A: cis-2-ethyl-4-(methoxycarbonyl)cyclopentanecarboxylic acid

Ruthenium (III) chloride hydrate (0.203 g, 0.900 mmol) was added to amixture of 5-ethylbicyclo[2.2.1]hept-2-ene (5.00 g, 40.9 mmol,ChemSampCo) and sodium periodate (35.0 g, 164 mmol) in water (117 mL),MeCN (78 mL) and EtOAc (78 mL). The reaction mixture was stirred atambient temperature for about 16 h. The reaction mixture was filtered,extracted with Et₂O (2×100 mL). The aqueous layer was further extractedwith Et₂O (3×100 mL). The organic layers were combined, washed withbrine (100 mL), dried over anhydrous MgSO₄, filtered, and concd underreduced pressure. The residue was dissolved in Ac₂O (20 mL, 24 mmol) andheated at reflux for about 4 h. The reaction mixture was cooled toambient temperature and the solvent was removed under reduced pressure.MeOH (40 mL) was added and the reaction mixture was heated at reflux forabout 6 h. The solvent was removed under reduced pressure to yieldcis-2-ethyl-4-(methoxycarbonyl)cyclopentanecarboxylic acid (4.84 g, 59%)as a brown oil: LC/MS (Table 1, Method b) R_(t)=1.91 min; MS m/z: 201(M+H)⁺.

Step B: cis-3-tert-butyl 1-methyl 4-ethylcyclopentane-1,3-dicarboxylate

A mixture of cis-2-ethyl-4-(methoxycarbonyl)cyclopentanecarboxylic acid(4.50 g, 22.47 mmol) in SOCl₂ (8.20 mL, 112 mmol) was stirred at ambienttemperature for about 16 h. The solvent was removed under reducedpressure. The resulting residue was dissolved in t-BuOH (22.5 mL). Thereaction mixture was stirred at ambient temperature for about 16 h. Thesolvent was removed under reduced pressure. The residue was dissolved inwater (50 mL) and DCM (100 mL). The organic layer was separated, washedwith saturated aqueous NaHCO₃ (50 mL), dried over anhydrous Na₂SO₄,filtered, and concd under reduced pressure to give cis-3-tert-butyl1-methyl 4-ethylcyclopentane-1,3-dicarboxylate (3.94 g, 68%) as a darkbrown oil: LC/MS (Table 1, Method b) R_(t)=2.86 min; MS m/z: 257 (M+H)⁺.

Preparation #121-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)but-3-en-1-amine hydrochloride

Step A: (E)-2-styryl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine

To a solution of 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (3.1 g, 8.8mmol, Example #1, Step B), PdCl₂(dppf).DCM (0.719 g, 0.880 mmol) and(E)-styrylboronic acid (2.60 g, 17.6 mmol) in THF (3 mL) and water (2mL) was added Na₂CO₃ (2.33 g, 22.0 mmol). The reaction mixture wasdegassed with argon for about 5 min. The reaction mixture was heated atabout 50° C. After about 24 h, additional PdCl₂(dppf).DCM (0.719 g,0.880 mmol), (E)-styrylboronic acid (2.60 g, 17.6 mmol) and Na₂CO₃ (2.33g, 22.0 mmol) were added to the reaction mixture. After heating at about50° C. for about 48 h, the reaction mixture was cooled to ambienttemperature and diluted with DCM (200 mL) and water (200 mL). Theorganic layer was separated, dried over anhydrous Na₂SO₄, filtered, andconcd under reduced pressure. Purification by chromatography over silicagel eluting with a gradient of 20-60% EtOAc in heptane containing 5% DCMprovided (E)-2-styryl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine as a yellowsolid (1.2 g, 36%): LC/MS (Table 1, Method a) R_(t)=2.99 min; MS m/z:376 (M+H)⁺.

Step B: 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbaldehyde

To a solution of (E)-2-styryl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (1.2 g,3.2 mmol) in 1,4-dioxane (20 mL) and water (2.0 mL) was added sodiumperiodate (2.73 g, 12.8 mmol) followed by osmium tetroxide (2.5 wt % int-BuOH, 4.01 mL, 0.320 mmol). The reaction mixture was stirred for about1 day at ambient temperature and then additional sodium periodate (2.73g, 12.78 mmol) and osmium tetroxide (2.5 wt % in t-BuOH, 4.01 mL, 0.320mmol) were added. After stirring for about 2 days, a solution of 10%aqueous Na₂S₂O₃ (100 mL) and EtOAc (100 mL) was added. The organic layerwas separated, dried over anhydrous Na₂SO₄, filtered, and concd underreduced pressure to give a solid, which was triturated with heptane toremove benzaldehyde. The resulting solid was dried in vacuo to provide5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbaldehyde as a brown solid (0.77g, 80%): LC/MS (Table 1, Method a) R_(t)=2.01 min; MS m/z: 334 (M+H)⁺.

Step C: 1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)but-3-en-1-ol

To a solution of 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbaldehyde (5.1g, 17 mmol) in THF (100 mL) and water (33.3 mL) was added3-bromoprop-1-ene (2.86 mL, 33.9 mmol) followed by indium (3.89 g, 33.9mmol). The reaction mixture was stirred for about 15 h at ambienttemperature and then aqueous HCl (1 N, 150 mL) and EtOAc (150 mL) wereadded. The organic layer was separated, dried over anhydrous Na₂SO₄,filtered, concd in vacuo and purified by chromatography on silica geleluting with 20-60% EtOAc in heptane to provide1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)but-3-en-1-ol (4 g, 69%) as athick oil: LC/MS (Table 1, Method a) R_(t)=2.30 min; MS m/z: 344 (M+H)⁺.

Step D: 2-(1-azidobut-3-enyl)-5-tosyl-5H-pyrrolo[2,3-b]pyrazine

To a solution of 1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)but-3-en-1-ol(0.14 g, 0.41 mmol) in DCM (10 mL) was added thionyl chloride (0.045 mL,0.61 mmol). The reaction mixture was stirred for about 8 h at ambienttemperature and then EtOAc and saturated aqueous NaHCO₃ (10 mL each)were added. The organic layer was separated, dried over anhydrousNa₂SO₄, filtered and concd in vacuo. The crude chloride was dissolved inDMF (10 mL) and sodium azide (0.159 g, 2.45 mmol) was added to thereaction mixture. The reaction mixture was stirred for about 15 h atambient temperature and then EtOAc and saturated aqueous NaHCO₃ (10 mLeach) were added to the reaction mixture. The organic layer wasseparated, concd in vacuo, and purified by chromatography on silica geleluting with 10-60% EtOAc in heptane to provide2-(1-azidobut-3-enyl)-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (0.153 g, 87%)as an oil: LC/MS (Table 1, Method a) R_(t)=2.84 min; MS m/z: 369 (M+H)⁺.

Step E: 1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)but-3-en-1-aminehydrochloride

To a solution of 2-(1-azidobut-3-enyl)-5-tosyl-5H-pyrrolo[2,3-b]pyrazine(3.90 g, 10.6 mmol) in THF (60 mL) and water (30 mL) was addedtriphenylphosphine (3.33 g, 12.7 mmol). The reaction mixture was heatedto about 50° C. for about 15 h. The reaction mixture was cooled toambient temperature and concd in vacuo. The residue was dissolved inEtOAc (30 mL) and HCl (gas) was added until a pH of about 1 wasmaintained followed by the addition of Et₂O to induce precipitateformation. After stirring for about 15 h, the precipitate was collectedby filtration to provide1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)but-3-en-1-amine hydrochloride(2.5 g, 62%) as a tan solid: LC/MS (Table 1, Method a) R_(t)=1.80 min;MS m/z: 343 (M+H)⁺.

Preparation #13N-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)cyclohexanecarboxamide

To a slurry of (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanaminehydrochloride (0.50 g, 1.476 mmol, Example #5, Step C) in DCM (10 mL)was added cyclohexanecarbonyl chloride (0.221 mL, 1.623 mmol) followedby DIEA (0.644 mL, 3.69 mmol). The reaction mixture was stirred forabout 4 h at ambient temperature and then saturated aqueous NaHCO₃ (20mL) and DCM (20 mL) were added to the reaction mixture. The organiclayer was separated, concd in vacuo, and purified by chromatography onsilica gel (40 g) eluting with 20-80% EtOAc in DCM to provideN-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)cyclohexanecarboxamide(0.49 g, 80%) as a colorless solid: LC/MS (Table 1, Method a) R_(t)=2.40min; MS m/z: 413 (M+H)⁺.

Preparation #14* (2R,4S)-tert-butyl4-(cyclopropanesulfonamido)-2-methylpyrrolidine-1-carboxylate

To a slurry of 20 wt % Pd(OH)₂ on C (0.605 g, 0.862 mmol) in EtOH (75mL) was added a solution of (2R,4S)-tert-butyl4-azido-2-methylpyrrolidine-1-carboxylate (3.9 g, 17 mmol, synthesizedas described in Rosen, T.; Chu, D. T. W.; Lico, I. M.; Fernandes, P. B.;Marsh, K.; Shen, L.; Cepa, V. G.; Pernet, A. G. J. Med. Chem. 1988, 31,1598-1611) in EtOH (25 mL). The reaction mixture was sparged withhydrogen and an atmosphere of hydrogen was maintained via balloon. Thereaction mixture was stirred for about 2 h at ambient temperature andthen was filtered and concd in vacuo. The residue was dissolved in DCM(100 mL), cooled to about 0° C. and TEA (6.01 mL, 43.1 mmol) was addedfollowed by cyclopropanesulfonyl chloride (2.67 g, 19.0 mmol). Thereaction mixture was stirred at ambient temperature for about 15 h,saturated aqueous NaHCO₃ (50 mL) was added to the reaction mixture andthe organic layer was separated, concd in vacuo, and purified bychromatography on silica gel (80 g) eluting with 20-80% EtOAc in heptaneto provide (2R,4S)-tert-butyl4-(cyclopropanesulfonamido)-2-methylpyrrolidine-1-carboxylate (2.55 g,48%) as an oil: LC/MS (Table 1, Method a) R_(t)=1.98 min (ELSD); MS m/z:305 (M+H)⁺.

Preparation #15* (2R,4S)-tert-butyl4-(cyclopropanesulfonamido)-2-ethylpyrrolidine-1-carboxylate

To a slurry of 20 wt % Pd(OH)₂ on C (0.044 g, 0.062 mmol) in EtOH (30mL) was added a solution of (2R,4S)-tert-butyl4-azido-2-ethylpyrrolidine-1-carboxylate (1.5 g, 6.2 mmol, synthesizedas described in Rosen, T.; Chu, D. T. W.; Lico, I. M.; Fernandes, P. B.;Marsh, K.; Shen, L.; Cepa, V. G.; Pernet, A. G. J. Med. Chem. 1988, 31,1598-1611) in EtOH (10 mL). The reaction mixture was sparged withhydrogen and an atmosphere of hydrogen was maintained via balloon. Thereaction mixture was stirred for about 4 h at ambient temperature andthen was filtered and concd in vacuo. The residue was dissolved inpyridine (30 mL) and cyclopropanesulfonyl chloride (1.05 g, 7.49 mmol)was added. The reaction mixture was stirred for about 15 h at ambienttemperature and then was partitioned between EtOAc (50 mL) and saturatedaqueous CuSO₄ (50 mL). The organic layer was separated, washed withbrine (30 mL), dried over anhydrous Na₂SO₄, filtered, concd in vacuo,and purified by chromatography on silica gel (80 g) eluting with 20-80%EtOAc in heptane to provide (2R,4S)-tert-butyl4-(cyclopropanesulfonamido)-2-ethylpyrrolidine-1-carboxylate (0.95 g,48%) as an oil: LC/MS (Table 1, Method a) R_(t)=2.12 min (ELSD); MS m/z:319 (M+H)⁺.

Preparation #16 tert-butyl1-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrrolidin-3-ylcarbamate

To a solution of tert-butyl1-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamothioyl)-pyrrolidin-3-ylcarbamate(0.54 g, 1.0 mmol, Preparation #J.1) in THF (15 mL) was added DIEA(0.444 mL, 2.54 mmol) followed by mercury (II) trifluoroacetate (0.478g, 1.12 mmol). The reaction mixture was stirred at ambient temperaturefor about 2 h and then saturated aqueous NaHCO₃ (30 mL) and EtOAc (30mL) were added. The organic layer was separated, dried over anhydrousNa₂SO₄, filtered, and concd in vacuo. The crude material was purified bychromatography on silica gel (40 g) eluting with 10-40% EtOAc in DCM toprovide tert-butyl1-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrrolidin-3-ylcarbamate(0.411 g, 81%) as a yellow glass: LC/MS (Table 1, Method a) R_(t)=2.50min; MS m/z: 497 (M+H)⁺.

Preparation #17N-(4-(3-(2,3-dihydroxypropyl)-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)cyclopropanesulfonamide

To a solution ofN-(4-(3-allyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)bicyclo-[2.2.2]octan-1-yl)cyclopropanesulfonamide(0.27 g, 0.47 mmol, prepared using E with4-(tert-butoxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylic acid[Prime Organics], K with cyclopropylsulfonyl chloride, H fromPreparation #12, HATU and DIEA, Q with Lawesson's reagent and mercury(II) trifluoroacetate) in 1,4-dioxane (10 mL) and water (1 mL) was addedN-methylmorpholine-N-oxide (0.22 g, 1.8 mmol) followed by osmiumtetroxide (4 wt % in water, 0.36 mL, 0.047 mmol). The reaction mixturewas stirred for about 15 h and then DCM (20 mL) and water (10 mL) wereadded to the reaction mixture. The organic layer was separated, concd invacuo, and purified by chromatography on silica gel eluting with 10-50%MeCN in DCM, to provideN-(4-(3-(2,3-dihydroxypropyl)-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)cyclopropanesulfonamide(0.009 g, 3%): LC/MS (Table 1, Method a) R_(t)=1.90 min; MS m/z: 612(M−H)⁻.

Preparation #18 2-hydrazinyl-6-methyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine

Step A: 5-bromo-3-(prop-1-ynyl)pyrazin-2-amine

To a solution of 3,5-dibromopyrazin-2-amine (10.0 g, 39.5 mmol) in THF(200 mL) was added copper (I) iodide (0.377 g, 1.98 mmol),bis(triphenylphosphine)palladium (II) dichloride (1.39 g, 1.98 mmol) andTEA (16.5 mL, 119 mmol). The reaction mixture was cooled to about 0° C.and degassed with Ar. The reaction mixture was stirred for about 5 minand then the reaction mixture was sparged with propyne and a propyneatmosphere was maintained via balloon. The reaction mixture was stirredfor about 30 min at about 0° C. and then was allowed to warm to ambienttemperature. The reaction mixture was stirred for about 2 h and thenEtOAc (100 mL) and water (100 mL) were added to the reaction mixture.The organic layer was separated, dried over anhydrous Na₂SO₄, filtered,and concd in vacuo. The crude mixture was purified by chromatography onsilica gel (120 g) eluting with 10-60% EtOAc in DCM (dry loaded) toprovide 5-bromo-3-(prop-1-ynyl)pyrazin-2-amine (7.05 g, 84%) as a yellowsolid: LC/MS (Table 1, Method a) R_(t)=1.79 min; MS m/z: 212, 214 (1:1)(M+H)⁺.

Step B: 2-bromo-6-methyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine

To a slurry of NaH (60% dispersion in mineral oil, 2.00 g, 49.9 mmol) inNMP (100 mL) was slowly added a solution of5-bromo-3-(prop-1-ynyl)pyrazin-2-amine (7.05 g, 33.2 mmol) in NMP (20mL). The reaction mixture was stirred at ambient temperature for about20 min and then a solution of p-toluenesulfonyl chloride (6.97 g, 36.6mmol) in NMP (20 mL) was added. The reaction mixture was stirred atambient temperature for about 20 h and then aqueous HCl (1 N, 100 mL)was added to the reaction mixture. The resulting solids were collectedby filtration. The brown solid was triturated with DCM/EtOAc (1:1, 30mL) and collected by filtration to provide2-bromo-6-methyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (9.0 g, 74%) as abrown solid: LC/MS (Table 1, Method a) R_(t)=2.68 min; MS m/z: 366, 368(1:1) (M+H)⁺.

Step C: tert-butyl2-(6-methyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate

Tris(dibenzylideneacetone)dipalladium(0) (0.250 g, 0.273 mmol) and2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (0.232 g, 0.546mmol) were combined in 1,4-dioxane (15 mL). The flask was evacuated withsome bubbling of solvent and then carefully refilled with nitrogen (3times). Nitrogen was then bubbled directly into the reaction mixture.The mixture was then heated at about 80° C. for about 10 min and thenremoved from the heating source.2-Bromo-6-methyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (1.0 g, 2.73 mmol),tert-butyl hydrazinecarboxylate (0.541 g, 4.10 mmol) and NaOt-Bu (0.501mL, 4.10 mmol) were added and the reaction was heated at about 80° C.for about 1 h. The reaction was cooled to ambient temperature and thesolvents removed under reduced pressure. The black residue was thentaken up in EtOAc (50 mL) and filtered. The filtrate was washed withsaturated aqueous NH₄Cl (50 mL), EDTA (1.0 M aqueous, 50 mL) andsaturated aqueous NaHCO₃ (50 mL). The solution was dried over anhydrousNa₂SO₄, filtered, and concd under reduced pressure. The material waspurified by chromatography on silica gel (80 g) eluting with 25-100%EtOAc in heptane to provide tert-butyl2-(6-methyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate(0.160 g, 14%) as a brown oil: LCMS (Table 1, Method a) R_(t)=2.51 min;MS m/z: 418 (M+H)⁺.

Step D: 2-hydrazinyl-6-methyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine

tert-Butyl 2-(6-methyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate (0.16 g, 0.38 mmol) was stirred in 1,4-dioxane (1.9 mL) in asealed vial to give a brown solution. HCl (4 M in 1,4-dioxane, 0.958 mL,3.83 mmol) was added and the reaction stirred at ambient temperature forabout 20 h. The solvents were removed under reduced pressure. Theresidue was partitioned between saturated aqueous NaHCO₃ (10 mL) andEtOAc (10 mL). The layers were separated and the aqueous layer wasextracted with EtOAc (2×10 mL). The combined organic extracts werewashed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, andconcd in vacuo to provide2-hydrazinyl-6-methyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (0.089 g, 73%):LC/MS (Table 1, Method a) R_(t)=1.92 min; MS m/z: 318 (M+H)⁺.

Preparation #19 Preparation #19.1(1S,3R,4S)-3-methyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanaminePreparation #19.2(1S,3R,4S)-3-methyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine

To a mixture ofN-((1S,3R,4S)-3-methyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)acetamide(1.52 g, 3.36 mmol, prepared using Y from Example #7, step H and Pd/C,G, AA [Table 2, Method 3, It, =6.1 min, or ═ND], Z with NaOH, A withExample #1 Step D, HATU, and TEA, and B with TEA) and 1,4-dioxane (25mL) was added aqueous HCl (6 N, 25 mL, 150 mmol). The reaction washeated at about 100° C. for about 14 h and then was cooled to ambienttemperature and concd under reduced pressure. To the resulting brownresidue was added MeOH (30 mL) and the solution was concd under reducedpressure. To the resulting residue was added MeOH (5 mL) followed byslow addition of Et₂O (20 mL). Initially a cloudy solution formed andthen a dark oil/gum formed and the mixture was concd under reducedpressure. To the resulting brown residue was added MeOH (30 mL),(1S,3R,4S)-3-methyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentan-amine(1.35 g, 2.50 mmol, UV purity 75%) from a separate reaction, and silicagel (7 g). The mixture was concd under reduced pressure and purified bysilica gel chromatography eluting with a gradient of 0-100% (DCM/[2 MNH₃ in MeOH] (9:1)) in DCM, the column was further flushed with MeOHthen MeOH/aqueous NH₄OH (9:1), to give(1S,3R,4S)-3-methyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine[Preparation #19.1] (0.092 g, 5%) as a dark brown solid: LC/MS (Table 1,Method a) R_(t)=1.35 min; MS m/z: 257 (M+H)⁺ and 2.9 g of brown residuethat was partitioned between DCM and saturated aqueous NaHCO₃ (50 mLeach). The layers were separated and the aqueous layer was extractedwith additional DCM (2×50 mL). The combined organic layers were washedwith brine, dried over anhydrous MgSO4, filtered, and concd underreduced pressure to give(1S,3R,4S)-3-methyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine[Preparation #19.2] (1.94 g, 78%) as a taupe foam: LC/MS (Table 1,Method a) R_(t)=1.80 min; MS m/z: 411 (M+H)⁺.

Preparation #203-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylbenzoate

To a mixture of3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylbenzoate (5.00 g, 7.84 mmol, prepared from Example #4 Step J using IIwith benzoic acid, and B) in MeOH (16 mL) was added a solution ofpotassium cyanide (0.74 mL, 17.2 mmol) in MeOH (16 mL). The reaction wasstirred at ambient temperature for about 16 h. The reaction mixture wasconcd under reduced pressure to afford a residue. The residue waspartitioned between water (20 mL) and DCM (20 mL). The layers wereseparated and the aqueous layer was extracted with DCM (3×10 mL). Theextract was then washed with saturated aqueous NaHCO₃, dried overanhydrous MgSO₄, filtered, and concd under reduced pressure to afford acrude oil. The crude material was purified by silica gel chromatographyeluting with a gradient of 0-10% MeOH in DCM to3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylbenzoate (2.30 g, 78%) as a red tinted solid. LC/MS (Table 1, Method a)R_(t)=2.08 min; MS m/z: 376 (M+H)⁺.

Preparation #21 tert-butyl4-(aminomethyl)-2-ethylcyclopentanecarboxylate

Step A: tert-butyl 2-ethyl-4-(hydroxymethyl)cyclopentanecarboxylate

A solution of 3-tert-butyl 1-methyl4-ethylcyclopentane-1,3-dicarboxylate (3.88 g, 15.1 mmol, Preparation#11, Step B) in Et₂O (150 mL) was cooled to about −40° C. LAH (2 N inTHF, 8.32 mL, 16.6 mmol) was added dropwise. The reaction mixture wasstirred at about −40° C. for about 1 hour. The reaction mixture waspartitioned between saturated aqueous NaHCO₃ (50 mL) and EtOAc (3×50mL). The combined organic extracts were concd under reduced pressure.The crude material was purified by silica gel chromatography elutingwith a gradient of 0-100% EtOAc/heptane to give tert-butyl2-ethyl-4-(hydroxymethyl)cyclopentanecarboxylate (1.00 g, 29%) as abrown oil: LC/MS (Table 1, Method a) R_(t)=2.37 min; MS m/z: 229 (M+H)⁺.

Step B: tert-butyl2-ethyl-4-((methylsulfonyloxy)methyl)cyclopentanecarboxylate

To a solution of tert-butyl2-ethyl-4-(hydroxymethyl)cyclopentanecarboxylate (0.220 g, 0.964 mmol)in DCM (5 mL) was added TEA (0.16 mL, 1.15 mmol) and methanesulfonylchloride (0.083 mL, 1.06 mmol) at about 0° C. The reaction mixture wasallowed to warm to about 25° C. and stirred at about 25° C. for about 16h. The reaction mixture was partitioned between water (20 mL) and DCM(20 mL). The aqueous solution was washed with DCM (2×20 mL). Thecombined organic extracts were dried over anhydrous MgSO₄, filtered, andconcd under reduced pressure to give tert-butyl2-ethyl-4-((methylsulfonyloxy)methyl)cyclopentanecarboxylate (0.295 g,100%): LC/MS (Table 1, Method b) R_(t)=2.55 min; MS m/z: 307 (M+H)⁺.

Step C: tert-butyl 4-(aminomethyl)-2-ethylcyclopentanecarboxylate

To a solution of tert-butyl2-ethyl-4-((methylsulfonyloxy)methyl)cyclopentanecarboxylate (0.295 g,0.964 mmol) in DMF (5 mL) was added sodium azide (0.313 g, 4.82 mmol).The reaction was heated at about 50° C. for about 16 h and then cooledto about 15-20° C. Water (40 mL) was added to the reaction mixture. Theaqueous solution was extracted with DCM (3×30 mL). The combined organicextracts were dried over anhydrous MgSO₄, filtered, and concd underreduced pressure to give a dark brown oil. The brown oil was dissolvedin THF (6.5 mL) and water (3.5 mL). Triphenylphosphine (0.316 g, 1.205mmol) was added. The reaction mixture was stirred at about 25° C. forabout 15 h. The organic solvent was removed under reduced pressure andthe residue partitioned between saturated aqueous NaHCO₃ (20 mL) and DCM(20 mL). The organic phase was concd under reduced pressure. Theresulting residue was purified using silica gel chromatography elutingwith a gradient of 0-20% (20% (7 N ammonium in MeOH) in MeOH)) in DCM togive tert-butyl 4-(aminomethyl)-2-ethylcyclopentanecarboxylate (0.102 g,46%) as a brown oil: LC/MS (Table 1, Method b) R_(t)=1.72 min; MS m/z:228 (M+H)⁺.

Preparation #22 ethyl 2-ethyl-4-formylcyclopentanecarboxylate

Step A: 2-ethyl-4-(hydroxymethyl)cyclopentanecarboxylic acid

To a solution of 2-ethyl-4-(methoxycarbonyl)cyclopentanecarboxylic acid(8.34 g, 41.7 mmol, Preparation #11, Step A) in THF (208 mL) was addedLiBH₄ (0.907 g, 41.7 mmol) at about −20° C. The reaction mixture wasstirred at about −20° C. for about 1 h. The reaction mixture was allowedto warm to about 25° C. then was stirred at about 25° C. for about 16 h.Additional LiBH₄ (0.907 g, 41.7 mmol) was added. The reaction mixturewas stirred at about 25° C. for about 4 h. Water (10 mL) was addedslowly to quench the reaction. The solid was removed by vacuumfiltration. The filtrate was concd under reduced pressure. The resultingresidue was partitioned between water (50 mL) and DCM (3×50 mL). Thecombined organic extracts were dried over anhydrous MgSO₄, filtered, andconcd under reduced pressure to give2-ethyl-4-(hydroxymethyl)cyclopentanecarboxylic acid (7.29 g, 100%):LC/MS (Table 1, Method n) R_(t)=0.44 min; MS m/z: 173 (M+H)⁺.

Step B: ethyl 2-ethyl-4-(hydroxymethyl)cyclopentanecarboxylate

HCl gas was bubbled through a solution of2-ethyl-4-(hydroxymethyl)cyclopentanecarboxylic acid (7.29 g, 42.3 mmol)in EtOH (60 mL) at about 25° C. for about 10 min. The reaction mixturewas stirred at about 25° C. for about 72 h. The solvent was removedunder reduced pressure. The crude residue was partitioned between water(30 mL) and DCM (3×30 mL). The combined organic extracts were concdunder reduced pressure. The crude material was purified by silica gelchromatography eluting with a gradient of 0-100% EtOAc/heptane to giveethyl 2-ethyl-4-(hydroxymethyl)cyclopentanecarboxylate (4.89 g, 58%) asa yellow oil: ¹H NMR (CDCl₃) δ 4.23-4.02 (m, 2H), 3.74-3.47 (m, 2H),2.96-2.83 (m, 1H), 2.31-2.17 (m, 1H), 2.15-1.98 (m, 2H), 1.97-1.84 (m,1H), 1.79-1.66 (m, 1H), 1.65-1.50 (m, 1H), 1.49-1.37 (m, 1H), 1.30-1.21(m, 5H), 1.04-0.82 (m, 3H).

Step C: ethyl 2-ethyl-4-formylcyclopentanecarboxylate

To a solution of ethyl 2-ethyl-4-(hydroxymethyl)cyclopentanecarboxylate(4.84 g, 24.2 mmol) in DCM (100 mL) was added pyridinium chlorochromate(10.42 g, 48.3 mmol). The reaction mixture was stirred at about 25° C.for about 3 h. Silica gel (1 g) was added. The mixture was stirred atabout 25° C. for about 30 min. The solid was removed by vacuumfiltration, while rinsing with DCM (100 mL). The filtrate was concdunder reduced pressure. The resulting residue was purified using silicagel chromatography eluting with a gradient of 0-40% EtOAc/Heptane togive ethyl 2-ethyl-4-formylcyclopentanecarboxylate (3.03 g, 63%) as aclear oil: ¹H NMR (DMSO-d₆) δ 9.66-9.47 (m, 1H), 4.12-3.94 (m, 2H),2.94-2.73 (m, 2H), 2.19-1.90 (m, 4H), 1.55-1.65 (m, 1H), 1.37-1.23 (m,1H), 1.23-1.06 (m, 4H), 0.96-0.82 (m, 3H).

Preparation #23N-((1S,3R,4S)-3-ethyl-4-(8-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-N-((2-(trimethylsilyl)ethoxy)methyl)cyclopropanesulfonamide

Cesium carbonate (0.274 g, 0.841 mmol), tricyclohexylphosphine (20 wt %solution in toluene, 0.094 g, 0.067 mmol), Pd₂(dba)₃ (0.039 g, 0.042mmol) and trimethylborate (0.069 g, 0.547 mmol) were added to a solutionofN-((1S,3R,4S)-3-ethyl-4-(8-iodo-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-N-((2-(trimethylsilyl)ethoxy)methyl)cyclopropanesulfonamide(0.32 g, 0.421 mmol, prepared using KK from Preparation #GGG.1) in1,4-dioxane (8 mL). The mixture was degassed and heated at about 85° C.for about 2 h. The solvent was removed and the residue was partitionedbetween EtOAc and water (20 mL each). The organic phase was washed withbrine (15 mL), dried over anhydrous MgSO₄, filtered and concd. Theresulting mixture was purified by silica gel flash chromatography (40 to100% of EtOAc in heptane) to yieldN-((1S,3R,4S)-3-ethyl-4-(8-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-N-((2-(trimethylsilyl)ethoxy)methyl)cyclopropanesulfonamide(0.21 g, 77%) as a yellow amorphous solid. LC/MS (Table 1, Method a)R_(t)=3.39 min; MS m/z: 650 (M+H)⁺.

Preparation #24 diethyl2-(4-(cyclopropanesulfonamido)bicyclo[2.2.2]octan-1-yl)-2-oxoethylphosphonate

Step A: methyl4-(cyclopropanesulfonamido)bicyclo[2.2.2]octane-1-carboxylate

To a solution of methyl 4-aminobicyclo[2.2.2]octane-1-carboxylate (500mg, 2.73 mmol) (Yeh, V. S. C.; Kurukulasuriya, R.; Madar, D.; Patel, J.R.; Fung, S.; Monzon, K.; Chiou, W.; Wang, J.; Jacobson, P.; Sham, H.L.; Link, J. T. Bioorg. and Med. Chem. Let, 2006, vol. 16, i#20 p.5408-5413) in DCM (10 mL) at rt was added TEA (0.76 mL, 5.46 mmol) andDMAP (50 mg, 0.41 mmol). Cyclopropanesulfonyl chloride (764 mg, 5.46mmol, Matrix) was added dropwise by syringe. The reaction mixture wasstirred for about 15 h at rt. The mixture was washed with water (10 mL),and the aqueous layer was extracted with DCM (2×10 mL), the organiclayers were combined and dried over anhydrous Na₂SO₄, filtered and concdin vacuo. The crude materials was purified by silica gel chromatographyeluting with a gradient of 20-35% EtOAc in hexanes to afford methyl4-(cyclopropanesulfonamido)bicyclo[2.2.2]octane-1-carboxylate (410 mg,52% yield). LC/MS (Table 1, Method p) R_(t)=1.68 min; MS m/z: 288(M+H)⁺.

Step B: diethyl(4-(cyclopropanesulfonamido)bicyclo[2.2.2]octan-1-yl)methylphosphonate

A solution of diethyl methylphosphonate (1.27 g, 8.36 mmol) wasdissolved in THF (20 mL) and cooled to about −78° C. in a dryice-acetone bath under nitrogen. Then n-BuLi (9.77 mmol, 3.9 mL, 2.5M inhexane) was added dropwise over about 5 min. The reaction mixture wasstirred for about 3 h, keeping the temperature below about −70° C. Thena solution of methyl4-(cyclopropanesulfonamido)bicyclo[2.2.2]octane-1-carboxylate (800 mg,2.79 mmol) in THF (10 mL) was added, keeping the temperature at about−78° C. The solution was stirred for about 15 h, allowing thetemperature to rise slowly to rt. To the reaction mixture was addedsaturated aqueous NH₄Cl (30 mL) and extracted with EtOAc (3×30 mL). Theorganic layers were combined and washed with brine, dried over anhydrousNa₂SO₄ and concd to provide diethyl(4-(cyclopropanesulfonamido)bicyclo[2.2.2]octan-1-yl)methylphosphonate(1.30 g, 100% yield). The crude product was used in next step withoutfurther purification. LC/MS (Table 1, Method p) R_(t)=1.62 min; MS m/z:408 (M+H)⁺.

Preparation #253-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanone

Step A: ethyl 2-ethyl-4-oxocyclopentanecarboxylate

A round bottom flask was charged with ethyl2-ethyl-4-oxocyclopentanecarboxylate (1.5 g, 8.1 mmol, Example #22, StepB) in DCM (22 mL). To the flask were added ethylene glycol (0.91 mL, 16mmol), triethylorthoformate (2.0 mL, 12 mmol), and p-toluenesulfonicacid monohydrate (0.31 g, 1.6 mmol). The reaction mixture was stirred atrt for about 24 h. The solution was concd under reduced pressure to givea brown oil that was dissolved in EtOAc and purified by flash silica gelchromatography (Silicycle 25 g column) eluting with a gradient of 0-50%EtOAc in heptane. The product containing fractions were combined andconcd to dryness under reduced pressure to give ethyl2-ethyl-4-oxocyclopentanecarboxylate as a light yellow oil (1.6 g, 83%):LC/MS (Table 1, Method c) MS m/z 229 (M+H)⁺; ¹H NMR (CDCl) δ 4.14 (q,2H), 3.90 (m, 4H), 2.99 (q, 1H), 2.32-2.27 (m, 1H), 2.26-2.11 (m, 1H),2.05-1.99 (m, 1H), 1.96-1.91 (m, 1H), 1.83-1.78 (m, 1H), 1.46-1.39 (m,1H), 1.31-1.24 (m, 1H), 1.26 (t, 3H), 0.90 (t, 3H).

Step B: 8-ethyl-1,4-dioxaspiro[4.4]nonane-7-carboxylic acid

A round bottom flask was charged with ethyl8-ethyl-1,4-dioxaspiro[4.4]nonane-7-carboxylate (0.32 g, 1.4 mmol) andaqueous 1 N sodium hydroxide (14.0 mL, 14.0 mmol). The solution wasstirred overnight at rt. To the solution was added DCM (30 mL) followedby the addition of 20% aqueous citric acid (about 20 mL) to reach pH ofabout 2. The layers were separated and the aqueous solution wasextracted with DCM (2×30 mL) and DCM/EtOAc (1:1, 30 mL). The combinedextracts were dried over anhydrous MgSO₄, filtered, and concd underreduced pressure to give 8-ethyl-1,4-dioxaspiro[4,4]nonane-7-carboxylicacid as a clear, colorless oil (0.27 g, 96%): LC/MS (Table 1, Method c)R_(t)=1.20 min; MS m/z: 201 (M+H)⁺.

Step C:8-ethyl-N′-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,4-dioxaspiro[4.4]nonane-7-carbohydrazide

A 50 mL round bottom flask was charged with2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (0.350 g, 1.16 mmol,Example #1, Step D), 8-ethyl-1,4-dioxaspiro[4.4]nonane-7-carboxylic acid(0.250 g, 1.25 mmol), and DCM (6.0 mL). To the reaction mixture wasadded HATU (0.483 g, 1.27 mmol) and TEA (0.64 mL, 4.6 mmol) and theresulting yellow suspension was stirred at rt for about 3 h. To thereaction solution was added DCM (25 mL) and the solution was washed withwater and brine (20 mL each). The organic layer was dried over anhydrousMgSO₄, filtered, and concd under reduced pressure to give a brown oil.The crude product was purified by flash silica gel chromatography (25 gSilicycle column) eluting with a gradient of: 0-10% MeOH in DCM over 25min. The product containing fractions were concd under reduced pressureto give8-ethyl-N′-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,4-dioxaspiro[4.4]nonane-7-carbohydrazideas a foam (0.50 g, 89%): LC/MS (Table 1, Method c) R_(t)=1.49 min; MSm/z: 486 (M+H)⁺.

Step D:1-(8-ethyl-1,4-dioxaspiro[4.4]nonan-7-yl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine

A round bottom flask was charged with8-ethyl-N′-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,4-dioxaspiro[4.4]nonane-7-carbohydrazide(4.90 g, 10.1 mmol) and 1,4-dioxane (50 mL). To the flask was added DIEA(8.81 mL, 50.5 mmol) followed by the addition of thionyl chloride (0.770mL, 10.6 mmol). The mixture was heated to about 75° C. for about 90 min.Additional thionyl chloride (0.074 mL, 1.0 mmol) was added and heatingwas continued for about 1 h. The reaction was cooled to rt and stirredovernight. The solution was diluted with DCM (75 mL) and washed withwater (50 mL). The layers were separated and the organic layer was driedover anhydrous MgSO₄, filtered, and concd under reduced pressure to givea dark brown oil. The crude product was purified via flash silica gelchromatography eluting with a gradient of 0-60% acetone in heptane witha hold at 60% acetone in heptane. The product containing fractions werecombined and concd to give material that was loaded onto a second column(Silicycle, 40 g column), eluting with a gradient of 0-60% acetone inheptane. The product containing fractions were combined and concd underreduced pressure to give1-(8-ethyl-1,4-dioxaspiro[4.4]nonan-7-yl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineas a tan powder (3.0 g, 64%): LC/MS (Table 1, Method c) R_(t)=1.44 min;MS m/z: 468 (M+H)⁺.

Step E:3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanone

A round bottom flask was charged with1-((7S,8R)-8-ethyl-1,4-dioxaspiro[4.4]nonan-7-yl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine(3.56 g, 7.61 mmol) and THF (20 mL). To the solution was added aqueousHCl (6N, 3.81 mL, 22.8 mmol) and the mixture was stirred at rt for about2 h. The solvent was removed under reduced pressure and DCM (75 mL) andwater (50 mL) were added. The layers were separated and the organicsolution was dried over anhydrous MgSO₄, filtered, and concd underreduced pressure to give3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanoneas a brown foam (2.99 g, 93%): LC/MS (Table 1, Method c) R_(t)=1.40 min;MS m/z: 424 (M+H)⁺.

Preparation #26 3,3-difluoro-1-(vinylsulfonyl)pyrrolidine

A solution of 3,3-difluoropyrrolidine hydrochloride (0.3 g, 2.1 mmol,Matrix) and DIEA (0.37 mL, 2.1 mmol) in MeCN (5 mL) was stirred at about50° C. for about 30 min. The reaction was cooled to ambient temperatureand concd under reduced pressure. The solid was dissolved in MeCN (2 mL)and a solution of 2-chloroethanesulfonyl chloride (0.22 mL, 2.1 mmol) inEt₂O (3 mL) was added at about −78° C. and stirred for about 2 h. To thereaction mixture was added DIEA (0.6 mL, 3.4 mmol) and stirred for about1 h. The reaction was warmed to ambient temperature and the solvent wasremoved under reduced pressure. The residue was partitioned between DCM(5 mL) and water (2×2 mL). The combined organic layers were dried overanhydrous MgSO₄, filtered and concd under reduced pressure to give crude3,3-difluoro-1-(vinylsulfonyl)pyrrolidine (0.11 g, 27%) which was usedwithout further purification: LC/MS (Table 1, Method b) R_(t)=2.04 min;MS m/z: 198 (M+H)⁺.

Preparation #27 4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine

Step A: 4-chloro-3-iodo-5-nitropyridin-2-amine

A solution of 4-chloro-3-iodopyridin-2-amine (0.25 g, 0.982 mmol, BoaPharma) in concd H₂SO₄ (1.95 mL) was cooled to about 0° C. before theportion wise addition of potassium nitrate (0.21 g, 2.2 mmol) over 10min. The reaction was stirred for about 4 h at about 0° C. The reactionmixture was slowly pipetted over a solution of ammonium hydroxide andcrushed ice (10 mL) in an ice bath. The pH of the reaction wasmaintained above 9 by the incremental addition of ammonium hydroxide.The resulting precipitate was filtered and dried to afford4-chloro-3-iodo-5-nitropyridin-2-amine (0.085 g, 29%) as a green-tintedsolid LC/MS (Table 1, Method n) R_(t)=0.64 min; MS m/z: 298 (M−H)⁻.

Step B: 4-chloro-5-nitro-3-((trimethylsilyl)ethynyl)pyridin-2-amine

To a solution of 4-chloro-3-iodo-5-nitropyridin-2-amine (5.30 g, 17.7mmol) in THF (90 mL) was added TEA (15.0 mL, 108 mmol). The reactionmixture was degassed and purged with nitrogen 3 times.Bis(triphenylphosphine)-palladium(II)dichloride (0.62 g, 0.88 mmol,Strem), copper(I) iodide (0.17 g, 0.89 mmol), andtrimethylsilylacetylene (5.4 mL, 39 mmol) were added to the reactionmixture. The mixture was degassed and purged 3 times with nitrogen. Thereaction was heated at about 60° C. for about 16 h. The reaction mixturewas cooled to ambient temperature. The reaction mixture was filtered andwashed with THF (200 mL). The filtrate was concd under reduced pressure.DCM (100 mL) was added to the residue and the precipitate that formedwas filtered and collected to give4-chloro-5-nitro-3-((trimethylsilyl)ethynyl)pyridin-2-amine (0.77 g).The remaining filtrate was concd under reduced pressure and the crudematerial was purified by flash chromatography on silica gel eluting witha gradient of 0-100% EtOAc in DCM. The purified material was combinedwith the 0.77 g of precipitate to afford4-chloro-5-nitro-3-((trimethylsilyl)ethynyl)pyridin-2-amine (2.22 g,47%) as a yellow solid: LC/MS (Table 1, Method c) R_(t)=1.62 min; MS m/z268 (M−H)⁻.

Step C: 4-chloro-3-ethynyl-5-nitropyridin-2-amine

To a solution of4-chloro-5-nitro-3-((trimethylsilyl)ethynyl)pyridin-2-amine (1.98 g,7.34 mmol) in DMF (25 mL) was added potassium fluoride on alumina (40 wt%, 2.67 g, 18.35 mmol). The suspension was stirred at ambienttemperature for about 1 h. Activated charcoal (0.3 g) was added and thesuspension was filtered through Celite®, washing with DMF (150 mL). Thesolvent was removed under reduced pressure and the crude material waspurified by silica gel chromatography eluting with a gradient of 0-10%MeOH in DCM to afford 4-chloro-3-ethynyl-5-nitropyridin-2-amine (1.03 g,71%) as a yellow solid: LC/MS (Table 1, Method n) R_(t)=0.59 min; MSm/z: 196 (M−H)⁻.

Step D: 4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine

To a solution of 4-chloro-3-ethynyl-5-nitropyridin-2-amine (0.16 g, 0.81mmol) in DMF (3 mL) was added chloro(1,5-cyclooctadiene) rhodium (I)dimer (0.02 g, 0.04 mmol) and tris(4-fluorophenyl)phosphine (0.128 g,0.405 mmol). The reaction mixture was degassed by bubbling argon for 15min. The reaction mixture was heated at about 80° C. for about 45 min.The reaction was cooled to ambient temperature and the solvent wasremoved under reduced pressure and the residue was suspended in ether(10 mL). The precipitate was collected by filtration and dried to give4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (0.132 g, 83%, containsapproximately 6% mol of DMF and approximately 3% mol oftris(4-fluorophenyl)phosphine) as a brown solid: LC/MS (Table 1, Methoda) R_(t)=2.05 min; MS m/z 198 (M+H)⁺.

Preparation #28*N-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-2-methylpropane-2-sulfonamide

To a solution of(1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine(115 mg, 0.271 mmol, Preparation #BB.1*) in DCM (1.5 mL) was added DIEA(0.071 mL, 0.406 mmol) followed by 2-methylpropane-2-sulfinic chloride(0.037 mL, 0.298 mmol). After about 4 h the reaction mixture was dilutedwith EtOAc (10 mL) and aqueous saturated NaHCO₃ (10 mL). The organiclayer was separated, dried over anhydrous Na₂SO₄, filtered and concd invacuo. The crude residue was dissolved in DCM (1.5 mL) and a freshlyprepared solution of m-chloroperbenzoic acid (0.271 mL, 0.271 mmol, 1Min DCM) was added. After about 2 h the reaction mixture was diluted withEtOAc (10 mL) and saturated aqueous NaHCO₃ (10 mL). The organic layerwas separated, dried over anhydrous Na₂SO₄, filtered and concd in vacuo.The crude residue was purified by chromatography on silica gel elutingwith EtOAc to provideN-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-2-methylpropane-2-sulfonamide(95 mg, 64% yield) as an oil. LC/MS (Table 1, Method a) R_(t)=2.40 min;MS m/z: 545 (M+H)⁺.

Preparation #29*3-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)-4-methoxycyclobut-3-ene-1,2-dione

To a solution of(1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine(0.40 g, 0.942 mmol, Example #8 Step M) in MeOH (3 mL) was added3,4-dimethoxycyclobut-3-ene-1,2-dione (0.14 g, 0.98 mmol) and DIEA (0.18mL, 1.0 mmol). The reaction was stirred at rt for about 16.5 h. Then thesolid from the reaction mixture was collected via vacuum filtration,while washing with cold MeOH (about 4° C., 10 mL), and dried in a vacuumoven at about 60° C. to give crude3-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)-4-methoxycyclobut-3-ene-1,2-dione(0.36 g, 73%, 90% purity): LC/MS (Table 1, Method a) R_(t)=2.13 min; MSm/z: 535 (M+H)⁺.

Preparation #303,3,3-trifluoro-1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)propan-1-aminehydrochloride

Step A:N-(diphenylmethylene)-1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine

To a solution of (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine(2.00 g, 6.61 mmol, Example #5 Step C) in DCM (30 mL) was addeddiphenylmethanimine (1.16 mL, 6.61 mmol). After about 2 d, the reactionmixture was concd in vacuo to provideN-(diphenylmethylene)-1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine(2.75 g, 89%) as a foam and used without further purification. LC/MS(Table 1, Method a) R_(t)=3.02 min; MS m/z: 467 (M+H)⁺.

Step B:3,3,3-trifluoro-1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)propan-1-amine,hydrochloride

To a solution ofN-(diphenylmethylene)-1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine(0.722 g, 1.55 mmol) in THF (3 mL) at about −78° C. was added NaHMDS(0.5 M in THF, 1.55 mL, 1.55 mmol). After about 30 min,1,1,1-trifluoro-2-iodoethane (1.51 mL, 15.5 mmol) was added to thereaction mixture. After about 4 h, the reaction mixture was allowed towarm to rt slowly over night. After about 15 h, EtOAc (30 mL) andsaturated aqueous NaHCO₃ (30 mL) were added. The organic layer wasseparated, concd in vacuo and purified by chromatography on silica geleluting with EtOAc/heptane (20-50%) to provide the crude alkylatedimine. The imine was dissolved in isopropyl acetate (30 mL) and concdHCl (0.50 mL) was added. The reaction mixture was spun on a rotoryevaporator for 1 h prior to partial concentration to approx 10 mL.Additional isopropyl acetate (30 mL) was added and the solvent waspartially removed in vacuo until approx. 10 mL remained. Et₂O (30 mL)was added and the solution was allowed to age for about 30 min. Theresulting solids were collected by filtration and dried in vacuo toprovide3,3,3-trifluoro-1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)propan-1-aminehydrochloride (0.150 g, 23%) as a colorless solid. LC/MS (Table 1,Method a) R_(t)=1.88 min; MS m/z 385 (M+H)⁺.

Preparation #31(1S,2R,4R)-4-(2-ethoxy-2-oxoethyl)-2-ethylcyclopentanecarboxylic acid

Step A: (3R,4S)-3-ethyl-4-(hydroxymethyl)cyclopentanol

To a solution of (1S,2R)-ethyl 2-ethyl-4-oxocyclopentanecarboxylate (5g, 27.1 mmol, Example #22 step B) in THF (100 mL) at about −78° C. wasadded LAH (2 M in THF, 54.3 mL, 109 mmol). After about 1 h, the reactionmixture was allowed to warm to rt slowly. After about 4 h, water (4.8mL) followed by aqueous NaOH (15% w/v, 4.8 mL) followed by water (9.6mL) was added to the reaction mixture. After about 15 h, anhydrousNa₂SO₄ was added and the slurry was filtered and concd in vacuo toprovide crude (3R,4S)-3-ethyl-4-(hydroxymethyl)cyclopentanol (3.9 g,100%) as an oil which was used without further purification. LC/MS(Table 1, Method a) R_(t)=2.40 min; MS m/z: 145 (M+H)⁺.

Step B: (3R,4S)-3-ethyl-4-(hydroxymethyl)cyclopentanone

To a solution of (3R,4S)-3-ethyl-4-(hydroxymethyl)cyclopentanol (4.00 g,27.7 mmol) in MeCN (70 mL) and water (30.0 mL) was added potassiumbromate (1.487 mL, 29.1 mmol) and CAN (0.760 g, 1.387 mmol). Thereaction mixture was heated to about 80° C. After about 2 h, thereaction mixture was cooled to rt and Et₂O (100 mL) was added. Theorganic layer was separated, washed with brine (30 mL), concd in vacuoand purified by chromatography on silica gel eluting with EtOAc/heptane(20-60%) to provide (3R,4S)-3-ethyl-4-(hydroxymethyl)cyclopentanone (2.4g, 61%) as an oil. ¹H NMR (400 MHz, CDCl₃) δ 3.79 (dd, J=10.5, 5.3 Hz,1H), 3.70 (dd, J=10.5, 6.5 Hz, 1H), 2.55-2.44 (m, 1H), 2.41-2.25 (m,4H), 2.15-2.05 (m, 1H), 1.55-1.65 (m, 2H), 1.43-1.30 (m, 1H), 0.97 (t,J=7.3 Hz, 3H).

Step C:(3S,4R)-3-((tert-butyldimethylsilyloxy)methyl)-4-ethylcyclopentanone

To a solution of (3R,4S)-3-ethyl-4-(hydroxymethyl)cyclopentanone (2.60g, 18.3 mmol) in DMF (30 mL) was added imidazole (1.87 g, 27.4 mmol)followed by tert-butylchlorodimethylsilane (3.03 g, 20.1 mmol). Afterabout 4 h, heptane (50 mL) was added. The heptane layer was removed andwashed with brine. The brine layer was combined with the DMF layer andextracted with EtOAc/heptane (1:1, 30 mL). The heptane and EtOAc layerswere combined, concd in vacuo and purified by chromatography on silicagel eluting with EtOAc/heptane (0-30%) to provide(3S,4R)-3-((tert-butyldimethylsilyloxy)methyl)-4-ethylcyclopentanone(3.5 g, 75%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 3.77 (dd,J=10.5, 4.3 Hz, 1H), 3.64 (dd, J=10.5, 4.0 Hz, 1H), 2.40-2.20 (m, 5H),2.18-2.02 (m, 1H), 1.65-1.55 (m, 1H), 1.52-1.37 (m, 1H), 0.97 (t, J=7.4Hz, 3H), 0.87 (s, 9H), 0.43 (s, 3H), 0.03 (s, 3H).

Step D: ethyl2-((3S,4R)-3-((tert-butyldimethylsilyloxy)methyl)-4-ethylcyclopentylidene)acetate

To a slurry of NaH (60% dispersion in mineral oil, 0.608 g, 15.2 mmol)in THF (50 mL) was added ethyl 2-(diethoxyphosphoryl)acetate (3.25 mL,16.2 mmol). After about 30 min, the phosphonate solution was added to aflask charged with(3S,4R)-3-((tert-butyldimethylsilyloxy)methyl)-4-ethylcyclopentanone(2.6 g, 10.14 mmol). After about 20 h, EtOAc (20 mL) and saturatedaqueous NH₄Cl (20 mL) were added. The organic layer was removed concd invacuo and purified by chromatography on silica gel eluting withEtOAc/heptane (20-60%) to provide ethyl2-((3S,4R)-3-((tert-butyldimethylsilyloxy)methyl)-4-ethylcyclopentylidene)acetate(3.3 g, 100%) as an oil. LC/MS (Table 1, Method a) R_(t)=3.91, 3.96 min;MS m/z: 327 (M+H)⁺.

Step E: ethyl2-((3R,4S)-3-ethyl-4-(hydroxymethyl)cyclopentylidene)acetate

To a solution of ethyl2-((3S,4R)-3-((tert-butyldimethylsilyloxy)methyl)-4-ethylcyclopentylidene)acetate(1.00 g, 3.06 mmol) in THF (20 mL) was added TBAF (1M in THF, 4.59 mL,4.59 mmol). After 6 h, EtOAc and water were added. The organic layer wasseparated, concd in vacuo and purified by chromatography on silica geleluting with EtOAc/heptane to provide ethyl2-((3R,4S)-3-ethyl-4-(hydroxymethyl)cyclopentylidene)acetate (0.620 g,95%) as an oil. LC/MS (Table 1, Method a) R_(t)=1.96, 2.08 min; MS m/z:213 (M+H)⁺.

Step F: ethyl 2-((1R,3R,4S)-3-ethyl-4-(hydroxymethyl)cyclopentyl)acetate

To a solution of ethyl2-((3R,4S)-3-ethyl-4-(hydroxymethyl)cyclopentylidene)acetate (0.160 g,0.754 mmol) in DCM (3 mL) was added Crabtree's catalyst (0.030 g, 0.038mmol). The reaction mixture was sparged with hydrogen for about 5 minand an atmosphere of hydrogen was maintained via balloon. After about 24h, the reaction mixture was concd in vacuo and purified bychromatography on silica gel eluting with EtOAc/heptane (30-80%) toprovide ethyl 2-((1R,3R,4S)-3-ethyl-4-(hydroxymethyl)cyclopentyl)acetate(0.140 g, 87%) as an oil. ¹H NMR (400 MHz, CDCl₃) δ 4.12 (q, J=7.1 Hz,2H), 3.71-3.64 (dd, J=10.5, 8.0 Hz, 1H), 3.47 (dd, J=10.5, 8.0 Hz, 1H),2.55-2.41 (m, 1H), 2.32 (d, J=6.7 Hz, 2H), 2.02-1.89 (m, 1H), 1.88-1.76(m, 1H), 1.70-1.60 (m, 1H), 1.48-1.33 (m, 4H), 1.26 (t, J=7.1 Hz, 3H),1.22-1.07 (m, 1H), 0.90 (t, J=7.4 Hz, 3H).

Step G: (1S,2R,4R)-4-(2-ethoxy-2-oxoethyl)-2-ethylcyclopentanecarboxylicacid

To a solution of ethyl2-((1R,3R,4S)-3-ethyl-4-(hydroxymethyl)cyclopentyl)acetate (0.140 g,0.653 mmol) in MeCN (2 mL), water (4 mL) and EtOAc (2 mL) was addedsodium periodate (0.349 g, 1.633 mmol) followed by ruthenium(III)chloride hydrate (0.0015 g, 0.0065 mmol). After about 2 h, the reactionmixture was diluted with EtOAc (20 mL) and water (10 mL). The organiclayer was separated and extracted with aqueous NaOH (1 N, 10 mL). The pHof the aqueous layer was adjusted to about 1 with concd HCl andextracted with EtOAc (20 mL). The organic layer was dried over anhydrousMgSO₄, filtered, and concd in vacuo to provide(1S,2R,4R)-4-(2-ethoxy-2-oxoethyl)-2-ethylcyclopentanecarboxylic acid(0.150 g, 101%) as an oil which was used without further purification.¹H NMR (600 MHz, CDCl₃) δ 10.68 (bs, 1H), 4.13 (q, J=7.1 hz, 2H),2.99-2.95 (m, 1H), 2.76-2.64 (m, 1H), 2.31 (d, J=7.6 Hz, 2H), 2.24 (ddd,J=13.5, 8.7, 4.8 Hz, 1H), 2.18-2.11 (m, 1H), 1.81 (dt, J=13.0, 8.4 Hz,1H), 1.55-1.45 (m, 3H), 1.31-1.27 (m, 1H), 1.25 (t, J=7.0 Hz, 3H), (t,J=7.4 Hz, 3H).

Preparation #322,2,2-trifluoro-1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)ethanamine,hydrochloride

Step A:(S,E)-2-methyl-N-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylene)propane-2-sulfinamide

To a solution of 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbaldehyde (8.66g, 28.7 mmol, Preparation #12 Step B) and(S)-2-methylpropane-2-sulfinamide (4.18 g, 34.5 mmol) in DCM (20 mL) atambient temperature was added anhydrous powdered copper(II) sulfate(13.8 g, 86 mmol). After about 20 h, the reaction mixture was filteredand partially concd in vacuo. Heptane was added to the solution and theresulting solids were collected by filtration and dried in vacuo toprovide(S,E)-2-methyl-N-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylene)propane-2-sulfinamide(11.5 g, 99%) as a solid. LC/MS (Table 1, Method a) R_(t)=2.50 min; MSm/z: 405 (M+H)⁺.

Step B:(S)-2-methyl-N-(2,2,2-trifluoro-1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)ethyl)propane-2-sulfinamide

To a dry flask charged with 4 Å molecular sieves (5 g) andtetramethyl-ammonium fluoride (0.553 g, 5.93 mmol) was added THF (20mL). The reaction mixture was stirred for about 30 min after which itwas cooled to about −78° C. and a solution of(S,E)-2-methyl-N-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylene)propane-2-sulfinamide(1.20 g, 2.97 mmol) in THF (10 mL) was added. After about 15 mintrimethyl(trifluoromethyl)silane (0.877 mL, 5.93 mmol) was added to thereaction mixture. The mixture was allowed to warm to −35 to −45° C.After about 3 h, the reaction mixture was cooled to −78° C. and aqueousNH₄Cl was added. The reaction mixture was allowed to warm to rt. EtOAc(30 mL) and brine (30 mL) were added. The organic layer was separated,dried over anhydrous Na₂SO₄, filtered and concd in vacuo to providecrude(S)-2-methyl-N-(2,2,2-trifluoro-1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)ethyl)propane-2-sulfinamide(1.4 g, 99%) as a foamsulfonamide which was used without furtherpurification. LC/MS (Table 1, Method a) R_(t)=2.49 min; MS m/z 475(M+H)⁺.

Step C:2,2,2-trifluoro-1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)ethanaminehydrochloride

To a solution of(S)-2-methyl-N-(2,2,2-trifluoro-1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)ethyl)propane-2-sulfinamide(1.40 g, 2.95 mmol) in MeOH (20 mL) was added HCl (4 N in 1,4-dioxane,7.38 mL, 29.5 mmol). After about 2 h, the reaction mixture was partiallyconcd in vacuo and diluted with Et₂O until solids began to form. Afterabout 30 min, the resulting solids were collected by filtration anddried in vacuo to provide2,2,2-trifluoro-1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)ethanaminehydrochloride (0.840 g, 70%) as a solid. LC/MS (Table 1, Method a)R_(t)=2.16 min; MS m/z 371 (M+H)⁺.

Preparation #33(1S,2R,4S)-4-(dibenzylamino)-2-methylcyclopentanecarboxylic acid

Step A: (1S,2R,4S)-4-(dibenzylamino)-2-methylcyclopentanecarboxylate(R)-1-phenylethanamine

To a solution of 4-(dibenzylamino)-2-methylcyclopentanecarboxylic acid(1240 g, 1499 mmol, prepared using X with Example #24 Step H anddibenzylamine and TT) in THF (8.0 L) was added(R)-(+)-1-phenylethylamine (0.193 L, 1499 mmol). The mixture was warmedto reflux to dissolve the solids, and was then cooled to ambienttemperature. After about 15 h, the reaction mixture was filtered, washedTHF (800 mL) and dried in a vacuum oven to afford(1S,2R,4S)-4-(dibenzylamino)-2-methylcyclopentanecarboxylate(R)-1-phenylethanamine (565 g, 85%, 97. 5% ee): LC/MS (Table 2, Method70) R_(t)=8.49 min. The mother liquor was concd. The residue wasdissolved in THF (1 L), heated to dissolve the solids, and cooled toambient temperature. After about 15 h, the reaction mixture wasfiltered, washed THF (800 mL) and dried in a vacuum oven to affordadditional (1S,2R,4S)-4-(dibenzylamino)-2-methylcyclopentanecarboxylate(R)-1-phenylethanamine (78.5 g, 12%, 95.2% ee): HPLC (Table 2, Method70) R_(t)=8.57 min

Step B: (1S,2R,4S)-4-(dibenzylamino)-2-methylcyclopentanecarboxylic acid

Phosphoric acid (11.40 mL, 196 mmol) was added to a flask containingwater (500 mL). The solution was stirred for about 5 min.(1S,2R,4S)-4-(dibenzylamino)-2-methylcyclopentanecarboxylate(R)-1-phenylethanamine (83 g, 187 mmol) was added to the solution insmall portions. MTBE (500 mL) was added and the contents were mixedwell, dissolving the solid. The phases were settled and separated. Theaqueous layer was back extracted with MTBE (150 mL). The combinedorganic phases were dried over anhydrous sodium sulfate, filtered, andconcentrated in vacuo to afford(1S,2R,4S)-4-(dibenzylamino)-2-methylcyclopentanecarboxylic acid (60 g,99%) as an oil: HPLC (Table 1, Method x) R_(t)=4.57 min.

Preparation #34 3,3-difluorocyclobutane-1-sulfonyl chloride

Step A: 3-bromo-1,1-difluorocyclobutane

To a vigorously stirred solution of 3-bromocyclobutanone (18.0 g, 121mmol, prepared as described in J. Am. Chem. Soc., 1971, 93, 2481) in DCM(375 mL) at about 0° C. was added dropwise via an addition funnel DAST(36.9 mL, 279 mmol) over about 1 h. The reaction mixture continuedstirring at about 0° C. for about 2 h and at ambient temperature forabout 14 h. The reaction was cooled to about −5° C. in an ice/acetonebath and a saturated aqueous solution of NaHCO₃ (400 mL) was addeddropwise via addition funnel. The bilayers remained vigorously stirringfor about 1 h. The layers were partitioned and the aqueous layer wasextracted with DCM (4×200 mL). The combined organic layers were driedover anhydrous MgSO₄, filtered, and solvent removed under reducedpressure (180 mm Hg maximum, 30° C. water bath) to afford3-bromo-1,1-difluorocyclobutane (15.3 g, 59%) as a light brown oil asproduct: ¹H NMR (400 MHz, CDCl₃) δ 4.28-4.14 (m, 1H), 3.35-3.16 (m, 2H),3.06-2.87 (m, 2H).

Step B: S-3,3-difluorocyclobutyl ethanethioate

To a solution of 3-bromo-1,1-difluorocyclobutane (13.8 g, 64.7 mmol) inDMSO (24.6 mL) was added potassium thioacetate (22.2 g, 194 mmol). Thesolution was heated at about 45° C. for about 16 h. Water (20 mL) andEt₂O (50 mL) were added. The layers were partitioned and the aqueouslayer was extracted with Et₂O (7×50 mL). The combined organic layerswere dried over anhydrous MgSO₄, filtered, and solvent removed underreduced pressure (60 mm Hg maximum, 30° C. water bath) to afford crudeS-3,3-difluorocyclobutyl ethanethioate (13.09 g, 78%) as an oil: ¹H NMR(400 MHz, d₆-DMSO) δ 3.84-3.69 (m, 1H), 3.14 (ddd, J=13.0, 7.5, 3.9 Hz,2H), 2.66-2.55 (m, 2H), 2.33 (s, 3H).

Step C: potassium 3,3-difluorocyclobutane-1-sulfonate

To a solution of crude S-3,3-difluorocyclobutyl ethanethioate (13.0 g,39.1 mmol) in acetic acid (100 mL) was added H₂O₂ (24.0 mL, 235 mmol,30% in water). After about 4 h, an exotherm was noted which generatedenough heat to reflux the reaction mixture. After about 20 h, thereaction mixture was diluted with toluene (500 mL) and partially concdin vacuo. This process was repeated (5×). The solution was diluted withEtOH (about 500 mL) and KOH (4.4 g, 78 mmol) was added to the reactionmixture. The precipitate was collected by filtration and discarded.Additional KOH (4.4 g, 78 mmol) was added to the filtrate and theprecipitate was collected by filtration. The solution was partiallyconcd in vacuo. The solution was diluted with EtOH (approx. 500 mL) andpartially concd again (3×). The precipitate was collected by filtration.The last 2 collected solids were dried in vacuo and combined to providepotassium 3,3-difluorocyclobutane-1-sulfonate (3.5 g, 42.6%). AdditionalKOH (4.39 g, 78 mmol) and the solution was partially concd in vacuo. Thesolution was diluted with EtOH (approx. 500 mL) and concd again (3×).The resulting solids were collected by filtration to provide potassium3,3-difluorocyclobutane-1-sulfonate (1.6 g, 19%): ¹H NMR (400 MHz,d₆-DMSO) δ 3.01 (ddd, J=13.5, 6.3, 2.5 Hz, 1H), 2.72-2.59 (m, 4H).

Step D: 3,3-difluorocyclobutane-1-sulfonyl chloride

To a suspension of potassium 3,3-difluorocyclobutane-1-sulfonate (0.250g, 1.189 mmol) in thionyl chloride (2.60 mL, 35.7 mmol) was added DMF (3drops). The reaction was heated to about 60° C. for about 21 h. Thesolvent was removed under reduced pressure and the residue was used inthe next reaction without further workup or purification to afford crude3,3-difluorocyclobutane-1-sulfonyl chloride (0.227 g, 100%) as product.¹H NMR (400 MHz, CDCl₃) δ 4.33-4.17 (m, 1H), 3.28 (dd, J=11.1, 7.6 Hz,2H), 3.21-3.05 (m, 2H).

Preparation #35 isopropyl(1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylcarbamate

To a solution of(1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine(0.080 g, 0.19 mmol, Preparation #BB.1*) in THF (2 mL) was added TEA(0.079 mL, 0.565 mmol) and the solution was stirred at ambienttemperature for about 10 min. To the reaction was added isopropylchloroformate (1 M in toluene, 0.18 mL, 0.18 mmol) and the reactionmixture was stirred for about 1 h. The solvent was removed under reducedpressure and DCM (5 mL) and saturated aqueous NaHCO₃ (2 mL) were added.The layers were separated and the organic layer was washed with brine (2mL), dried over MgSO₄, filtered and concentrated under reduced pressureto give crude isopropyl(1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylcarbamate(0.080 g, 60%) which was used without further purification: LC/MS (Table1, Method b) R_(t)=2.33 min; MS m/z: 511 (M+H)⁺.

Preparation #36 3-(aminomethyl)cyclobutanecarboxylic acid

To a flask charged with 10% palladium on carbon (0.20 g, 0.19 mmol) wasadded a solution of benzyl 3-(azidomethyl)cyclobutanecarboxylate (2.00g, 8.15 mmol, prepared using IIII from benzyl3-(hydroxymethyl)cyclobutanecarboxylate (Parkway Scientific), JJJJ withsodium azide) in MeOH (100 mL). The reaction mixture was sparged withhydrogen and an atmosphere of hydrogen was maintained via a balloon. Thereaction mixture was stirred for about 4 h at ambient temperature andthen was filtered through a pad of Celite®, washed with MeOH andconcentrated in vacuo to give the crude3-(aminomethyl)cyclobutanecarboxylic acid (1.08 g, 100%) which was usedwithout further purification: LC/MS (Table 1, Method r) R_(t)=2.41 min(ELSD); MS m/z: 130 (M+H)⁺.

Preparation #37 ethyl3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-7-carboxylate

3-Bromo-2-oxo-propionic acid ethyl ester (0.090 mL, 0.72 mmol) was addedto a mixture of 5-tosyl-5H-pyrrolo[3,2-b]pyrazin-2-amine (0.180 g, 0.624mmol, prepared using E from Example #3 Step E and HCl) and 1,4-dioxane(3.5 mL) under nitrogen. After about 3 days, the volatiles were removedunder reduced pressure. The residue was slurried in Et₂O (5 mL) and thenfiltered to afford a tan powder. The solid was slurried in MeCN (3.50mL) under nitrogen. PFPAA (0.40 mL, 2.1 mmol) was added. After about 30min, the volatiles were removed under reduced pressure. The residue wasdissolved in DCM (20 mL) and washed with saturated aqueous NaHCO₃/water(2:1, 20 mL). The aqueous layer was extracted with DCM (20 mL). Thecombined organics were dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by silicagel chromatography eluting with a gradient of 20-100% EtOAc/heptane toafford ethyl3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-7-carboxylate (0.181 g,75%): LC/MS (Table 1, Method n) R_(t)=0.70 min; MS m/z: 385 (M+H)⁺.

Preparation #386H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-8-carbaldehyde

Water (1.0 mL) was added to a mixture of6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.200 g, 1.26 mmol,prepared using D from Preparation #BBBBB.1 and NaOH) andhexamethylenetetramine (0.264 g, 1.89 mmol). Acetic acid (0.5 mL) wasadded. The reaction vessel was sealed and the mixture was warmed toabout 100° C. After about 8 h, the solution was allowed to cool toambient temperature. After sitting for about 13 h, the mixture wascooled to about 0° C. The resulting mixture was diluted with water (1mL) and then filtered rinsing with water. The solid was dried to afford6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-8-carbaldehyde (0.041 g,18%): LC/MS (Table 1, Method n) R_(t)=0.23 min; MS m/z 188 (M+H)⁺.

Preparation #39 2-(4-methylpiperazin-1-yl)-4-(tributylstannyl)pyrimidine

1-Methylpiperazine (0.160 mL, 1.44 mmol) was added to a solution of2-(methylsulfonyl)-4-(tributylstannyl)pyrimidine (0.250 g, 0.481 mmol,synthesized as described in Majeed, A. J., et al. Tetrahedron 1989, 45,993-1006) and 1,4-dioxane (1.0 mL) under nitrogen. After about 2 h, thesolution was warmed to about 50° C. After about 30 min, the solution waswarmed to about 80° C. After about 30 min, a reflux condenser wasattached and the solution was warmed to about 100° C. After about 16 h,the brown solution was allowed to cool to ambient temperature. Water (5mL) was added. The mixture was extracted with EtOAc (2×5 mL). Thecombined organics were dried over anhydrous Na₂SO₄, filtered, andconcentrated. The residue was purified by silica gel chromatographyeluting with a gradient of 2-10% MeOH/DCM to afford2-(4-methylpiperazin-1-yl)-4-(tributylstannyl)pyrimidine (0.127 g, 56%):¹H NMR (400 MHz, CDCl₃) δ 8.07 (d, J=4.6 Hz, 1H), 6.63 (d, J=4.6 Hz,1H), 3.98-3.82 (m, 4H), 2.63-2.48 (m, 4H), 2.40 (s, 3H), 1.70-1.43 (m,6H), 1.42-1.20 (m, 6H), 1.18-0.97 (m, 6H), 0.88 (t, J=7.3 Hz, 9H).

Preparation #402-(4-methylpiperazin-1-yl)-4-(tributylstannyl)quinazoline

Step A: 4-chloro-2-(4-methylpiperazin-1-yl)quinazoline

2,4-Dichloroquinazoline (2.00 g, 10.1 mmol, prepared as described inPrasad, M., et al. Org. Process Res. Dev. 2004, 8, 330-340) was slurriedin 1,4-dioxane (20.0 mL). 1,4-Dimethylpiperazine (1.44 mL, 10.6 mmol)was added. The mixture was heated in a CEM microwave at about 150° C.for about 5 min. The material was poured into saturated aqueousNaHCO₃/water (1:1, 150 mL). The mixture was extracted with EtOAc (5×100mL). 20 g of silica gel was added to the combined organics and thevolatiles were removed under reduced pressure. The resulting solid waspurified by silica gel chromatography eluting with a gradient of 2-10%MeOH/DCM to afford 4-chloro-2-(4-methylpiperazin-1-yl)quinazoline (1.36g, 52%): LC/MS (Table 1, Method n) R_(t)=0.51 min; MS m/z 263 (M+H)⁺.

Step B: 4-iodo-2-(4-methylpiperazin-1-yl)quinazoline

Hydrogen iodide (55% aqueous solution, 4.00 mL, 29.3 mmol) was slowlyadded to 4-chloro-2-(4-methylpiperazin-1-yl)quinazoline (1.36 g, 5.18mmol) under air while cooling in an ambient temperature water bath.After about 5 min, the bath was removed, the reaction vessel was wrappedin aluminum foil, and the mixture was stirred at ambient temperature forabout 5 h. DCM (4.0 mL) was added and the mixture was stirred for about39 h. Hydrogen iodide (55% aqueous solution, 8.0 mL, 110 mmol) was addedand the mixture was stirred for about 71 h. The mixture was slowly addedto saturated aqueous NaHCO₃ (200 mL) and EtOAc (200 mL). Aftercompletion of the quench, the layers were separated. The organics werewashed with saturated aqueous NaHCO₃/water (1:1, 200 mL). The organicswere dried over anhydrous Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by silica gel chromatographyeluting with a gradient of 2-5% MeOH/DCM to afford (1.18 g, 69%) as a3:1 mixture of 4-iodo-2-(4-methylpiperazin-1-yl)quinazoline to4-chloro-2-(4-methylpiperazin-1-yl)quinazoline.4-iodo-2-(4-methylpiperazin-1-yl)quinazoline: LC/MS (Table 1, Method n)R_(t)=0.55 min; MS m/z 355 (M+H)⁺.

Step C: 2-(4-methylpiperazin-1-yl)-4-(tributylstannyl)quinazoline

Bis(triphenylphosphine)palladium(II) acetate (0.063 g, 0.085 mmol) wasadded to 3:1 mixture of4-iodo-2-(4-methylpiperazin-1-yl)quinazoline:4-chloro-2-(4-methylpiperazin-1-yl)quinazoline(0.300 g) under nitrogen. Bis(tributyltin) (0.855 mL, 1.69 mmol) wasadded. TBAF (1.0 M solution in THF, 2.54 mL, 2.54 mmol) was added. Themixture was purged with nitrogen for about 20 min and then stirred undernitrogen at ambient temperature for about 7 h. Saturated aqueousNaHCO₃/water (1:1, 20 mL) and EtOAc (50 mL) were added. The mixture wasfiltered through a syringe filter, the layers were separated and theorganics were washed with water (2×10 mL). The organics were dried overanhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography eluting with agradient of 5-10% MeOH/DCM to afford a sticky brown solid. The materialwas dissolved in EtOAc (10 mL) and washed with water (2×5 mL). Theorganics were dried over anhydrous Na₂SO₄, filtered, and concentrated toafford a 1:1 mix of2-(4-methylpiperazin-1-yl)-4-(tributylstannyl)quinazoline:4-chloro-2-(4-methylpiperazin-1-yl)quinazoline(0.058 g, 17%).2-(4-methylpiperazin-1-yl)-4-(tributylstannyl)quinazoline: ¹H NMR (400MHz, DMSO-d₆) δ 7.69-7.64 (m, 1H), 7.61-7.57 (m, 1H), 7.49-7.44 (m, 1H),7.31-7.26 (m, 1H), 3.95-3.83 (m, 4H), 2.44-2.35 (m, 4H), 2.22 (s, 3H),1.66-1.48 (m, 6H), 1.37-1.18 (m, 12H), 0.82 (t, J=7.3 Hz, 9H).

Preparation #41 4-(methylsulfonyl)morpholine

To a solution of morpholine (2.00 mL, 22.96 mmol) in DCM (40 mL) wasadded TEA (3.20 mL, 22.96 mmol) at about −20° C., then methanesulfonylchloride (2.68 mL, 34.4 mmol) was added dropwise at about −20° C. Thereaction mixture was stirred at about −20° C. for about 2 h, then warmedto rt. The mixture was partitioned with saturated aqueous NH₄Cl (100 mL)and DCM (3×50 mL). The combined organic layers were concentrated andpurified by silica gel chromatography eluting with a gradient of 0-100%EtOAc/heptane to give 4-(methylsulfonyl)morpholine (3.95 g, 100%) as awhite solid: ¹H NMR (DMSO-d₆) δ 3.70-3.60 (m, 4H), 3.12-3.04 (m, 4H),2.89 (s, 3H).

Preparation #42 methyl 5-(chloromethyl)-3-methylfuran-2-carboxylate

To a solution of methyl 3-methylfuran-2-carboxylate (8.00 g, 57.1 mmol)in DCM (285 mL) was added zinc chloride (2.14 g, 15.7 mmol) andparaformaldehyde (2.2 mL, 82 mmol). The solution was warmed to about 35°C. HCl gas was bubbled through the reaction mixture for about 20 min.The mixture was partitioned with water (50 mL) and DCM (3×30 mL). Thecombined organic layers were concentrated and purified by silica gelchromatography eluting with a gradient of 0-50% EtOAc/heptane to givemethyl 5-(chloromethyl)-3-methylfuran-2-carboxylate (8.24 g, 77%) as awhite solid: LC/MS (Table 1, Method n) R_(t)=0.69 min; MS m/z: 189(M+H)⁺.

Preparation #43 cis-methyl5-((t-butoxycarbonylamino)methyl)-3-methyltetrahydrofuran-2-carboxylate

A solution of methyl 5-(azidomethyl)-3-methylfuran-2-carboxylate (3.10g, 15.88 mmol, prepared using General Procedure JJJJ from Preparation#42 and sodium azide) in MeOH (50 mL) was added to a suspension of 5%Rh/C (0.31 g, 3.01 mmol) and di-tert-butyl dicarbonate (4.16 g, 19.06mmol) in a 50 mL pressure bottle. The reaction mixture was stirred under40 psi of hydrogen at about 50° C. for about 3.5 days. The mixture wasfiltered through a nylon membrane. The organic solvent was concentratedunder reduced pressure to give cis-methyl5-((t-butoxycarbonylamino)methyl)-3-methyltetrahydrofuran-2-carboxylate(4.19 g, 81%) as a brown oil: ¹H NMR (CDCl₃) δ 5.70 (s, 1H), 4.43-4.46(d, 1H), 4.28-4.12 (m, 1H), 3.75 (s, 3H), 3.50-3.30 (m, 2H), 2.75-2.55(m, 1H), 1.95-2.05 (m, 1H), 1.65-1.48 (m, 1H), 1.45 (s, 9H), 1.03-0.97(d, 3H).

Preparation #44(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamineand(1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine

To a mixture ofN-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)acetamide(5.0 g, 10.7 mmol, Example #8 Step L) and THF (110 mL) was added aqueousHCl (6 N, 63 mL, 375 mmol). The reaction was heated at about 95° C. forabout 20 h and then cooled to ambient temperature and concd underreduced pressure. To the resulting brown residue was added DCM (100 mL)and the solution was washed with saturated NaHCO₃ (3×50 mL). The aqueousportion was extracted with DCM (3×50 mL). The combined organic layerswere washed with brine (100 mL), dried over anhydrous MgSO₄, filtered,and concd under reduced pressure. The material was purified bychromatography on silica gel eluting with 0-100% DCM/MeOH/NH₄OH(950:45:5) to give a mixture of(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamineand(1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine(3.2 g, 70%) in a 1:10 ratio based on H-NMR as an off-white solid: LC/MS(Table 1, Method a) R_(t)=1.75 min; MS m/z: 425 (M+H)⁺.

Preparation #45 Methyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylate

CO was bubbled into an orange solution of2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (50.0 g, 142 mmol, Example #7,step B) in DMF (2.50 L) within a 5 L round bottom flask for about 2 min.Bis(triphenylphosphine)-palladium(II) dichloride (9.96 g, 14.2 mmol),TEA (59 mL, 423 mmol) and MeOH (173.0 mL, 4259 mmol) were added and theflask was fitted with a balloon of CO. The mixture was heated at about95° C. under an atmosphere of CO (1 atmosphere). After stirringovernight, the reaction mixture was cooled to ambient temperatureovernight and poured into ice water (3.2 L). The mixture was stirred forabout 10 min and the precipitate was collected by filtration, whilewashing with water, and dried for 1 h. The crude material was dissolvedin DCM, separated from residual water, dried over anhydrous MgSO₄,filtered, added silica gel, and concd under reduced pressure to preparefor chromatography. The crude material was purified by silica gel columnchromatography eluting with 0-5% MeOH in DCM to yield methyl5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylate with 5 mol % DCM as anexcipient (40.7 g, 86%, 93% purity): LC/MS (Table 1, Method a)R_(t)=2.35 min; MS m/z 332 (M+H)⁺.

Preparation #46 5-Tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylic acid

HCl (6 N aqueous, 714 mL) was added to a yellow solution of methyl5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylate (17.8 g, 53.6 mmol,Preparation #45) in 1,4-dioxane (715 mL) within a 2 L round bottomflask, and the mixture was heated at about 60° C. for about 16 h. Thereaction mixture was cooled to ambient temperature. The organic solventwas removed under reduced pressure and the precipitate was collected,washed with water, and dried to yield5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylic acid (14.4 g, 85%) as ayellow solid: LC/MS (Table 1, Method a) R_(t)=1.63 min; MS m/z 316(M−H)⁻.

Preparation #47 tert-Butyl5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate

In a 500 mL round bottom flask,5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylic acid (14.4 g, 45.3 mmol,Preparation #46), diphenylphosphoryl azide (9.78 mL, 45.3 mmol) and TEA(13.9 mL, 100 mmol) in t-BuOH (200 mL) were added to give an orangesuspension. The mixture was heated at about 70° C. for about 16 h,cooled to ambient temperature and the insoluble material was filteredoff. The solvent was removed under reduced pressure and the crudematerial was purified by silica gel column chromatography eluting with25-60% EtOAc in heptane over 30 min to yield tert-butyl5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (9.75 g, 54%) as anoff-white solid: LC/MS (Table 1, Method a) R_(t)=2.79 min; MS m/z 389(M+H)⁺.

Preparation #482-bromo-1-(4-(dibenzylamino)-2-methylcyclopentyl)ethanone

Oxalyl chloride (4.37 mL, 49.9 mmol) was slowly added to a solution of4-(dibenzylamino)-2-methylcyclopentanecarboxylic acid (7.34 g, 22.7mmol, Example #7, step I) in DCM (100 mL), (note: mild gas evolution)followed by a dropwise addition of DMF (0.26 mL, 3.41 mmol). The mixturewas stirred at ambient temperature for about 14 h. The solvent wasremoved under reduced pressure to yield a beige amorphous solid, whichwas dissolved in THF and MeCN (1:1, 100 mL) and added to a solution oftrimethylsilyldiazomethane (2 M in Et₂O, 39.7 mL, 79 mmol) in THF andMeCN (1:1, 100 mL) at about 0° C. The resulting mixture was stirred atabout 0° C. for about 3 h and then was quenched by a dropwise additionof HBr (48% aqueous, 25 mL, 221 mmol). The resulting mixture wasneutralized by a dropwise addition of saturated aqueous NaHCO₃ (300 mL)and the layers were separated. The organic layer was dried overanhydrous MgSO₄ and concd under reduced pressure. The residue waspurified by silica gel flash chromatography eluting with 5% to 45% ofEtOAc in heptane to yield2-bromo-1-(4-(dibenzylamino)-2-methylcyclopentyl)ethanone (6.3 g, 69%)as a yellow oil: LC/MS (Table 1, Method a) R_(t)=2.90 min; MS m/z 400,402 (M+H)⁺.

Preparation #49 tert-Butyl2-(4-(dibenzylamino)-2-methylcyclopentyl)-2-oxoethyl(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)carbamate

A solution of tert-butyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate(0.59 g, 1.519 mmol, Example #7, Step C) in DMF (5 mL) was addeddropwise to a suspension of NaH (60% dispersion in mineral oil, 0.058 g,1.45 mmol) in DMF (5 mL), at about 0° C. The resulting mixture wasstirred at about 0° C. for about 30 min and then added dropwise to asolution of 2-bromo-1-(4-(dibenzylamino)-2-methylcyclopentyl)ethanone(0.73 g, 1.8 mmol) in DMF (10 mL) at about 0° C. The resulting mixturewas stirred at about 0° C. for about 1 h and the solvent was removedunder reduced pressure. The residue was partitioned between saturatedaqueous NaHCO₃ and EtOAc (100 mL each). The organic phase was separated,dried over anhydrous MgSO₄ and concd under reduced pressure to yieldtert-butyl2-(4-(dibenzylamino)-2-methylcyclopentyl)-2-oxoethyl(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)carbamate(1.04 g, 97%) as a yellow amorphous solid: LC/MS (Table 1, Method a)R_(t)=3.30 min; MS m/z 708 (M+H)⁺.

Preparation #501-(4-(dibenzylamino)-2-methylcyclopentyl)-2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)ethanone

tert-Butyl2-(4-(dibenzylamino)-2-methylcyclopentyl)-2-oxoethyl(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)carbamate(6.19 g, 8.75 mmol, Preparation #49) was dissolved in HCl (4 N in1,4-dioxane, 25 mL). The reaction mixture was stirred at ambienttemperature for about 2 h. The solvent was removed under reducedpressure and the residue partitioned between saturated aqueous NaHCO₃and EtOAc (100 mL each). The organic phase was washed with brine (80mL), dried over anhydrous MgSO₄ and concd under reduced pressure toyield1-(4-(dibenzylamino)-2-methylcyclopentyl)-2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)ethanone(5.2 g, 98%) as a brown amorphous solid: LC/MS (Table 1, Method a)R_(t)=3.00 min; MS m/z 608 (M+H)⁺.

Preparation #51N,N-dibenzyl-3-methyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentanamine

A mixture of1-(4-(dibenzylamino)-2-methylcyclopentyl)-2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)ethanone(5.32 g, 8.75 mmol, Preparation #50) and Lawesson's reagent (1.88 g,4.64 mmol) was heated at about 60° C. for about 2 h. Lawesson's reagent(1.88 g, 4.64 mmol) was added. The reaction mixture was stirred at about60° C. for about 1 h. The solvent was removed under reduced pressure andthe residue purified by silica gel flash chromatography eluting with agradient of 0-8% MeOH in DCM to yieldN,N-dibenzyl-3-methyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentanamine(4.47 g, 87%) as a brown amorphous solid: LC/MS (Table 1, Method a)R_(t)=2.99 min; MS m/z 590 (M+H)⁺.

Preparation #52N,N-dibenzyl-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentanamine

N,N-Dibenzyl-3-methyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentan-amine(4.47 g, 7.58 mmol, Preparation #51) was dissolved in 1,4-dioxane (40mL). NaOH (2 N aqueous, 4 mL) was added and the reaction mixture washeated at about 90° C. for about 80 min. The organic solvent was removedunder reduced pressure and the residue was treated with saturatedaqueous NH₄Cl (70 mL) and extracted with DCM (2×60 mL). The combinedorganic extracts were washed with brine (70 mL), dried over anhydrousMgSO₄ and concd under reduced pressure. Purification by silica gel flashchromatography eluting with a gradient of 0-8% MeOH in DCM yieldedN,N-dibenzyl-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentan-amine(1.84 g, 56%) as a yellow oil: LC/MS (Table 1, Method a) R_(t)=2.31 min;MS m/z 436 (M+H)⁺.

Preparation #533-(3H-Imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentanamine

To a mixture ofN,N-dibenzyl-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentanamine(1.84 g, 4.22 mmol, Preparation #52) in EtOH (50 mL) was added 20 wt %Pd(OH)₂ on C (0.43 g, 0.61 mmol) and the resulting mixture was shakenunder hydrogen pressure of about 50 psi on a Parr shaker at about 50° C.for about 2 h. The catalyst was filtered off using a pad of Celite®, 20wt % Pd(OH)₂ on C (0.43 g, 0.61 mmol) was added, and the mixture wasshaken under hydrogen pressure of about 50 psi on a Parr shaker at about50° C. for about 16 h. The catalyst was filtered off using a pad ofCelite®, 20 wt % Pd(OH)₂ on C (0.43 g, 0.61 mmol) was added, and themixture was shaken under hydrogen pressure of about 50 psi on a Parrshaker at about 50° C. for about 4 h. The catalyst was filtered offusing a pad of Celite® and the filtrate was concd under reduced pressureto yield3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentanamine(0.88 g, 82%) as an off-white amorphous solid: LC/MS (Table 1, Method a)R_(t)=0.75 min and 0.87 min; MS m/z 256 (M+H)⁺.

General Procedure a: Formation of a Hydrazide from a Carboxylic Acid

To a mixture of a 2-hydrazinylpyrrolo[2,3-b]pyrazine (preferably 1equiv) and a carboxylic acid (1-2 equiv, preferably 1.1-1.3 equiv) in anorganic solvent (such as DCM, DMF or THF, preferably DMF) is added acoupling agent such as EDC.HCl or HATU (1.0-2.0 equiv, preferably1.2-1.6 equiv) with or without an organic base (such as TEA or DIEA, 2-5equiv, preferably 3-4 equiv). After about 1-72 h (preferably 2-16 h) atabout 20-60° C. (preferably about ambient temperature), the reaction isworked up using one of the following methods. If DMF is the solvent, thereaction is first concd under reduced pressure. Method 1: Water is addedand the layers are separated. Optionally, the mixture may be filteredthrough Celite® prior to the separation of the layers. The aqueous layeris then extracted with an organic solvent such as EtOAc or DCM. Thecombined organic layers are optionally washed with brine, dried overanhydrous Na₂SO₄ or MgSO₄, filtered or decanted, and concd under reducedpressure. Method 2: The reaction is diluted with an organic solvent suchas EtOAc or DCM and is washed with either water or brine or both. Theaqueous layer is optionally further extracted with an organic solventsuch as EtOAc or DCM. Then the organic layer or combined organic layersare optionally washed with brine, dried over anhydrous Na₂SO₄ or MgSO₄,filtered or decanted, and concd under reduced pressure. Method 3: Thereaction is diluted with an organic solvent such as EtOAc or DCM andwater is added. The layers are separated and the organic layer is concdunder reduced pressure and directly purified by chromatography.

Illustration of General Procedure A Preparation #A.1* (S)-tert-butyl3-(2-oxo-2-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinyl)ethyl)pyrrolidine-1-carboxylate

To a solution of (S)-3-carboxymethyl-pyrrolidine-1-carboxylic acidtert-butyl ester (0.756 g, 3.30 mmol, AstaTech) and2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (1.0 g, 3.3 mmol, Example#1, Step D) in DMF (33 mL) was added TEA (1.38 mL, 9.89 mmol) followedby the addition of HATU (1.25 g, 3.30 mmol). The resulting mixture wasstirred at ambient temperature for about 15 h then concd under reducedpressure. The residue was taken up in EtOAc (100 mL) and washed withwater (100 mL). The organic portion was separated, washed with brine(100 mL), dried over anhydrous Na₂SO₄, filtered, and concd under reducedpressure to give (S)-tert-butyl3-(2-oxo-2-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinyl)ethyl)pyrrolidine-1-carboxylateas a sticky brown solid (1.90 g, 100%). This material was used withoutfurther purification: LC/MS (Table 1, Method c) R_(t)=1.38 min; MS m/z:515 (M+H)⁺.

General Procedure B: Cyclization of a Hydrazide

To a solution of a 2-hydrazidyl-5H-pyrrolo[2,3-b]pyrazine (preferably 1equiv) in an organic solvent (for example 1,4-dioxane) is added a base(such as TEA or DIEA, 1-5 equiv, preferably 2-4 equiv) and SOCl₂ (1-5equiv, preferably 1-2 equiv). The mixture is heated at about 60-100° C.(preferably about 80° C.) for about 1-16 h (preferably about 1-2 h). Thereaction mixture is cooled to ambient temperature and worked up usingone of the following methods. Method 1: An organic solvent (such asEtOAc or DCM) and water are added. The layers are separated and theaqueous layer is optionally extracted with additional organic solvent.The combined organic layers may be optionally washed with aqueous base(such as NaHCO₃) and/or brine, dried over anhydrous Na₂SO₄ or MgSO₄,then decanted or filtered prior to concentrating under reduced pressure.Method 2: An organic solvent (such as EtOAc or DCM) is added and theorganic layer is optionally washed with brine or water, dried overanhydrous MgSO₄ or Na₂SO₄, filtered or decanted, and concd under reducedpressure. Method 3: The reaction mixture is partitioned between anorganic solvent (such as EtOAc or DCM) and saturated aqueous NaHCO₃ orbrine, dried over anhydrous Na₂SO₄ or MgSO₄, then decanted or filteredprior to concentrating under reduced pressure.

Illustration of General Procedure B Preparation #B.1* tert-butyl(1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylcarbamate

To a solution of tert-butyl(1S,3R)-3-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclopentylcarbamate(9.30 g, 18.1 mmol, prepared using A from Example #1 Step D, and(1R,3S)-3-tert-butoxycarbonylamino)cyclopentanecarboxylic acid[Peptech]) in 1,4-dioxane (100 mL) was added TEA (10.0 mL, 72.3 mmol)and SOCl₂ (2.11 mL, 28.9 mmol). The mixture was heated at about 80° C.for about 1.5 h. The reaction mixture was cooled to ambient temperature,EtOAc (200 mL) and water (200 mL) were added, and the layers wereseparated. The aqueous portion was extracted with EtOAc (2×100 mL) andthe combined organic extracts were washed with saturated aqueous NaHCO₃(100 mL) and brine (100 mL), dried over anhydrous Na₂SO₄, filtered, andconcd under reduced pressure. The crude material was purified by silicagel chromatography eluting with a gradient of 25-100% EtOAc in DCM togivetert-butyl-(1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylcarbamate(7.65 g, 85%): LC/MS (Table 1, Method a) R_(t)=2.37 min; MS m/z: 497(M+H)⁺.

General Procedure C: Cyclization of a Hydrazide with Loss ofBoc-Protecting Group

To a solution of an appropriately substituted2-hydrazidyl-5H-pyrrolo[2,3-b]pyrazine containing a Boc protecting group(preferably 1 equiv) and TEA or DIEA (0-6 equiv, preferably 4 equiv) inan organic solvent (such as 1,4-dioxane or DCM, preferably 1,4-dioxane)is added SOCl₂ (2.0-6.0 equiv, preferably 2.5 equiv). The reaction isheated at about 60-120° C. (preferably about 80-90° C.) for about 1-8 h(preferably about 2-4 h) and then worked up using one of the followingmethods. Method 1: The reaction mixture is filtered and washed with asuitable organic solvent (such as EtOAc or DCM) to give the targetcompound with no further purification. Method 2: The crude material isdiluted with a suitable organic solvent (such as EtOAc or DCM) andsaturated aqueous NaHCO₃ is added, the layers are separated and theorganic portion is dried over anhydrous Na₂SO₄ or MgSO₄, filtered, andconcd under reduced pressure. Method 3: The reaction mixture is washedwith a basic aqueous solution (preferably saturated aqueous NaHCO₃) andfiltered to give the Boc-deprotected target compound with no furtherpurification. If partial Boc-deprotection occurs, the filtrate isextracted with a suitable organic solvent (such as EtOAc or DCM), thelayers are separated and the organic portion is dried over anhydrousNa₂SO₄ or MgSO₄, filtered, and concd under reduced pressure to give theremaining Boc-protected compound. The crude Boc-protected material orpartially Boc-protected material obtained above is dissolved in1,4-dioxane or DCM (preferably 1,4-dioxane) and added to a solution ofHCl in an organic solvent (1-6 N, preferably 4 N HCl in 1,4-dioxane) andheated to about 30-60° C. (preferably about 50° C.) for about 1-5 h(preferably about 3 h). If a precipitate forms, it is collected and thendissolved in a suitable organic solvent (such as EtOAc or DCM) andwashed with a basic aqueous solution (preferably saturated aqueousNaHCO₃). If no precipitate forms, the reaction mixture is washed with abasic aqueous solution (preferably saturated aqueous NaHCO₃). In eithercase, the layers are separated and the organic portion is dried overanhydrous Na₂SO₄ or MgSO₄, filtered, and concd under reduced pressure.

Illustration of General Procedure C Preparation #C.14-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-amine

To a solution of tert-butyl4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)-bicyclo[2.2.2]octan-1-ylcarbamate(6.1 g, 11.0 mmol, Example #9, Step E), and TEA (6.1 mL, 44.0 mmol) in1,4-dioxane (110 mL) was added SOCl₂ (2.0 mL, 27.5 mmol). The reactionmixture was heated at about 80° C. for about 2 h then cooled to ambienttemperature. The reaction mixture was washed with saturated aqueousNaHCO₃ (3×50 mL). The layers were separated and the aqueous portion wasfiltered to give4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]-octan-1-amineas a brown solid (1.17 g, 24%): LC/MS (Table 1, Method a) R_(t)=1.28min; MS m/z: 437 (M+H)⁺. The remaining filtrate was extracted with EtOAc(10 mL). The combined organic layer was dried over anhydrous MgSO₄,filtered, and concd under reduced pressure to afford crude tert-butyl4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-ylcarbamate(3.5 g). The crude Boc-protected material was dissolved in 1,4-dioxane(38 mL) and HCl (4 N in 1,4-dioxane, 8 mL) was added. The reactionmixture was heated to about 50° C. for about 3 h. The precipitate formedwas collected by filtration. The solid was dissolved in DCM (50 mL), andwashed with saturated aqueous NaHCO₃ (3×20 mL). The layers wereseparated and the organic portion was dried over anhydrous MgSO₄,filtered, and concd under reduced pressure to give additional4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-amineas a brown solid (2.3 g, 50% over 2 steps): LC/MS (Table 1, Method a)R_(t)=1.28 min; MS m/z: 437 (M+H)⁺.

General Procedure D: Hydrolysis of a Sulfonamide

To a flask containing a sulfonamide, for example, a sulfonyl-protectedpyrrole, (preferably 1 equiv) in an organic solvent (such as1,4-dioxane, MeOH, or THF/MeOH, preferably 1,4-dioxane) is added anaqueous base (such as aqueous Na₂CO₃ or aqueous NaOH, 1-30 equiv,preferably 2-3 equiv for aqueous NaOH, preferably 15-20 equiv foraqueous Na₂CO₃). The mixture is stirred at about 25-100° C. (preferablyabout 60° C.) for about 1-72 h (preferably about 1-16 h). In cases wherethe reaction does not proceed to completion as monitored by TLC, LC/MS,or HPLC, additional aqueous base (such as aqueous Na₂CO₃, 10-20 equiv,preferably 10 equiv or aqueous NaOH, 1-5 equiv, preferably 1-2 equiv)and/or a cosolvent (such as EtOH) is added. The reaction is continued atabout 25-100° C. (preferably about 60° C.) for about 0.25-3 h(preferably about 1-2 h). In any case where an additional base labilegroup is present (for example, an ester a trifluoromethyl, or a cyanogroup), this group may also be hydrolyzed. The reaction is worked upusing one of the following methods. Method 1. The organic solvent isoptionally removed under reduced pressure and the aqueous solution isneutralized with the addition of a suitable aqueous acid (such asaqueous HCl). A suitable organic solvent (such as EtOAc or DCM) andwater are added, the layers are separated, and the organic solution isdried over anhydrous Na₂SO₄ or MgSO₄, filtered, and concd to drynessunder reduced pressure to give the target compound. Method 2. Theorganic solvent is optionally removed under reduced pressure, a suitableorganic solvent (such as EtOAc or DCM) and water are added, the layersare separated, and the organic solution is dried over anhydrous Na₂SO₄or MgSO₄, filtered, and concd to dryness under reduced pressure to givethe target compound. Method 3. The reaction mixture is concd underreduced pressure and directly purified by one of the subsequent methods.

Illustration of General Procedure D Preparation #D.1*(3R,4R)-tert-butyl-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidine-1-carboxylate

To a solution of (3R,4R)-tert-butyl4-methyl-3-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate(40 g, 78 mmol, Example #5 Step H) in 1,4-dioxane (160 mL) was addedNaOH (1 N aqueous, 157 mL). The reaction was heated at about 60° C. forabout 1 h. The reaction was allowed to cool to ambient temperature. Thereaction was neutralized with aqueous HCl (4 N, 50 mL). The layers andextracted with DCM (2×300 mL). The combined organic extracts were washedwith brine (400 mL), dried over anhydrous Na₂SO₄, filtered then concd invacuo. The product was purified by chromatography on silica gel (330 g)using 1-5% MeOH in DCM to give (3R,4R)-tert-butyl3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidine-1-carboxylate(30 g, 99%): LC/MS (Table 1, Method b) R_(t)=2.00 min; MS m/z: 356(M+H)⁺.

TABLE D.1 Examples prepared using General Procedure D with NaOH R_(t)min (Table 1, m/z ESI+ Sulfonamide Product Ex # Method) (M + H)⁺(S)-1-((1-(cyclopropylsulfonyl) pyrrolidin-3-yl)methyl)-6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazine (prepared usingC from Preparation #A.1, and K with cyclopropanesulfonyl chloride andTEA)

D.1.1* 1.34 (a) 347 N-(1-((6-tosyl-6H- pyrrolo[2,3-e][1,2,4]triazolo[4,3-a] pyrazin- 1-yl)methyl)cyclobutyl)-cyclopropanesulfonamide (prepared using A from Example #1 Step D and2-(1- (terf-butoxycarbonyl-amino) cyclobutyl)acetic acid [prepared asdescribed in Eur. J. Med.Chem, 1999, 34, 363] with EDC•HCl, B with TEA,E with HCl, K with cyclopropanesulfonyl chloride and DIEA)

D.1.2 1.60 (a) 347 N-((1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo [4,3-a]pyrazin-1- yl)cyclopentyl)cyclo-propanecarboxamide (prepared using E from Preparation #B.1 with HCl, Hwith cyclopropanecarboxylic acid, EDC, and DIEA)

D.1.3* 1.15 (c) 311 2-cyclopropyl-N- ((1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)acetamide (prepared using using E from Preparation #B.1with HCl, H with cyclopropylacetic acid [Lancaster], EDC, and DIEA)

D.1.4* 1.17 (c) 325 4-fluoro-N-((1R,3R)- 3-(6-tosyl- 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)aniline (preparedusing PP with Example #2 Step F, 4- fluorophenyl boronic acid, and DIEA)

D.1.5* 1.91 (a) 337 4-chloro-N-((1R,3R)- 3-(6-tosyl- 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)aniline (preparedusing PP with Example #2 Step F, 4- chlorophenylboronic acid and DIEA)

D.1.6* 2.07 (a) 353 3,4-dichloro-N-((1R,3R)- 3-(6-tosyl- 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)aniline (preparedusing PP with Example #2 Step F, 3,4- dichlorophenylboronic acid andDIEA)

D.1.7* 2.24 (a) 387 4-methoxy-N-((1R,3R)-3-(6- tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin- 1-yl)cyclopentyl)aniline (prepared usingPP with Example #2 Step F, 4- methoxyphenyl boronic acid and DIEA)

D.1.8* 1.74 (a) 349 4-methoxy-N-(4- methoxyphenyl)- N-((1R,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e] [1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)aniline (prepared using PP with Example #2 Step F, 4-methoxyphenyl boronic acid and DIEA)

D.1.9* 2.30 (a) 455 N-((1S,3R,4S)-3-ethyl-4-(6- tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)azetidine-1-sulfonamide (Preparation #DD.1)

D.1.10* 1.81 (a) 390 N-((1S,3R,4S)-3-ethyl-4-(6- tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)-3,3-difluoroazetidine-1- sulfonamide (prepared using DD with Example #8Step M, 3,3-difluoroazetidine-1- sulfonyl chloride [prepared from CCwith 3,3- difluoroazetidine hydrochloride [Matrix] and DIEA] and TEA)

D.1.11* 1.97 (a) 426 (S)-N-((1S,3R,4S)-3- ethyl-4-(6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-2- (trifluoromethyl)pyrrolidine- 1-sulfonamide(prepared using DD with Example #8 Step M, (S)-2-(trifluoromethyl)pyrrolidine- 1-sulfonyl chloride [prepared from CC with(S)-(−)-2- (trifluoromethyl)pyrrolidine and DIEA] and TEA)

D.1.12* 2.13 (a) 472 N-((1S,3R,4S)-3-ethyl- 4-(6-tosyl- 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)-3,3-difluoropyrrolidine-1- sulfonamide (prepared using DD with Example#8 Step M, 3,3-difluoropyrrolidine-1- sulfonyl chloride [prepared fromCC with 3,3- difluoropyrrolidine hydrochloride and DIEA] and TEA)

D.1.13* 1.98 (a) 440 N-((1S,3R,4S)-3-ethyl- 4-(6-tosyl- 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)-4,4-difluoropiperidine-1- sulfonamide (prepared using DD with Example #8Step M, 4,4-difluoropiperidine-1- sulfonyl chloride [prepared from CCwith 4,4- difluoropiperidine hydrochloride and DIEA] and TEA)

D.1.14* 2.01 (a) 454 N-((1S,3R,4S)-3-methyl-4- (6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)aniline (preparedusing PP from Preparation #19.2, phenylboronic acid, and DIEA)

D.1.15* 2.01 (a) 333 4-methyl-N-((1S,3R,4S)-3- methyl-4-(6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)aniline(prepared using PP from Preparation #19.2, p- tolylboronic acid andDIEA)

D.1.16* 2.08 (a) 347 4-chloro-N-((1S,3R,4S)-3- methyl-4-(6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)aniline (prepared using PP from Preparation #19.2, 4-chlorophenylboronic acid, and DIEA)

D.1.17* 2.25 (a) 367 4-fluoro-N-((1S,3R,4S)-3- methyl-4-(6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)aniline (prepared using PP from Preparation #19.2, 4-fluorophenylboronic acid, and DIEA)

D.1.18* 2.05 (a) 351 1-(3,3-difluorocyclobutyl)-6- tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (prepared using H from Example #5 Step C and3,3- difluorocyclobutanecarboxylic acid [Waterstone], HATU, and DIEA; Qwith Lawesson's reagent and mercury (II) trifluoroacetate)

D.1.19* 1.63 (b) 249 4-((cis-3-(6-tosyl-6H- imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1- yl)cyclobutoxy)methyl)benzo- nitrile (prepared using H fromExample #5 Step C and Preparation #1 with HATU and DIEA; Q withLawesson's reagent and mercury (II) trifluoroacetate)

D.1.20* 1.81 (a) 344 N-((1S,3R,4S)-3-ethyl- 4-(6-tosyl- 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)- N-methyl-cyclopropanesulfonamide (prepared using A from Example #1 Step D andPreparation #Z.1 with HATU and TEA, B with TEA, S with iodomethane andNaH)

D.1.21* 1.75 (a) 389 N-(cyclopropylmethyl)-N- ((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)cyclo- propanesulfonamide (prepared using A from Example#1 Step D and Preparation #Z.1 with HATU and TEA, B with TEA, S with(bromomethyl)- cyclopropane and NaH)

D.1.22* 1.98 (a) 429 1-methyl-N-((1S,3R,4S)-3- methyl-4-(6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)-1H-pyrazole-4-sulfonamide (prepared using K from Preparation #19.2,1-methyl- 1H-pyrazole-4-sulfonyl chloride [Oakwood] and DIEA)

D.1.23* 1.60 (a) 401 N-(1S,3R,4S)-3-ethyl- 4-(6-tosyl- 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)-3,3,3-trifluoropropane-1- sulfonamide (prepared using K from Example #8Step M and 3,3,3-trifluoropropane-1- sulfonyl chloride [Matrix] andDIEA)

D.1.24* 2.05 (a) 431 N-(3S,5R)-5-ethyl-1- (3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3- e]pyrazin-8-yl)pyrrolidin-3-yl)cyclopropanesulfonamide (prepared using S from Example #3 Step E andtert- butyl bromoacetate, E with HCl, H with Preparation #E.1, OO)

D.1.25* 1.60 (a) 375 N-((1R,3S,4R)-3-ethyl-4-(6- tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)cyclopentane-sulfonamide and N- ((1S,3R,4S)-3-ethyl-4-(6- tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)cyclopentane-sulfonamide (prepared using K from Preparation #Y.1 andcyclopentanesulfonyl chloride, Z with NaOH, A with Example #1 Step D,HATU, and TEA, B with TEA)

 

D.1.26 1.77 (a) 403 (1S,3R)-1-[3-(6-tosyl-6H- pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)- isothiazolidin-2-yl-1,1-dioxide]cyclopentane (Preparation #2)

D.1.27* 1.47 (a) 347 1-((1R,3S)-3-(1H-pyrrol-1-yl)cyclopentyl)-6-tosyl-6H- pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazine (Preparation #3)

D.1.28* 1.82 (a) 293 N-(4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)bicyclo[2.2.2]octan-1-yl)azetidine-1-sulfonamide (prepared using DD with Example #9, Step Fand Preparation #CC.1)

D.1.29* 1.44 (a) 402 3,3-difluoro-N-(4-(6-tosyl-H-pyrrolo[2,3-e][1,2,4]triazolo [4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1- yl)azetidine-1-sulfonamide (Preparation #5)

D.1.30 1.61 (a) 438 2-(N-((1S,3R,4S)-3- ethyl-4-(6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)cyclo- propanesulfonamido)ethyl acetate (prepared using Afrom Preparation #Z.1, Example #1, Step D, HATU, and TEA, B with TEA, Swith 2-bromoethyl acetate)

D.1.31* 1.54 (a) 419 1-((1S,2R,4S)-2-ethyl-4-(4- methoxybenzyloxy)cyclo-pentyl-6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazine and1-((1R,2S,4R)- 2-ethyl-4-(4- methoxybenzyloxy)cyclo- pentyl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo [4,3-a]pyrazine (prepared using Z fromPreparation #EE.1, A from Example #1, Step D, HATU, and TEA, B withDIEA)

 

D.1.32 2.02 (b) 392 1-methyl-N-(4-(6-tosyl-6H- pyrrolo[2,3-e][1,2,4]triazolo [4,3-a]pyrazin-1- yl)bicyclo[2.2.2]octan-1-yl)cyclopropane-1- sulfonamide (prepared using K from Preparation #C.1and Preparation #6)

D.1.33 1.48 (a) 401 4-methyl-N-((1R,3R)- 3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4] triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)aniline (prepared using PP from Example #2, Step F and p-tolylboronic acid)

D.1.34* 1.89 (b) 333 N-((1S,3R,4S)-3-ethyl- 4-(6-tosyl- 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)-1-methylcyclopropane-1- sulfonamide (prepared using K from Example #8,Step M and Preparation #6)

D.1.35* 1.66 (a) 389 1-((1S,2R,4S)-4- (benzyloxy)-2-ethylcyclopentyl)-6-tosyl- 6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazine and 1-((1R,2S,4R)- 4-(benzyloxy)-2-ethylcyclopentyl)-6-tosyl- 6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazine (prepared using EE from benzyl 2,2,2- trichloroacetimidateand Preparation #FF.1)

 

D.1.36 2.15 (b) 362 N-(4-(6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)bicyclo[2.2.2]octan-1- yl)pyrrolidine-1-carboxamide(prepared using I from methyl 4-aminobicyclo[2.2.2]octane- 1-carboxylatehydrochloride [Prime Organics], pyrrolidine-1-carbonyl chloride and TEA,Z with NaOH, A from Example #1, Step D, HATU and TEA, B with TEA))

D.1.37 1.65 (a) 380 1-((1R,2R,4S)-2-ethyl-4-(4- methoxybenzyloxy)cyclo-pentyl)-6-tosyl-6H- pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazine and1-((1S,2S,4R)- 2-ethyl-4-(4- methoxybenzyloxy)cyclo- pentyl)-6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazine (prepared using Z fromPreparation #EE.1, A from Example #1, Step D, HATU, and TEA, B withDIEA)

 

D.1.38 2.14 (b) 392 N-(4-(6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)bicyclo[2.2.2]octan-1- yl)cyclobutanesulfonamide(prepared using K from methyl 4- aminobicyclo[2.2.2]octane-1-carboxylate hydrobromide [Prime Organics], cyclobutanesulfonyl chloride[Hande] and TEA, Z with NaOH, A from Example #1, Step D, HATU and TEA, Bwith TEA))

D.1.39 1.71 (a) 401 N-(4-(3-allyl-6-tosyl-6H-imidazo[1,5,-a]pyrrolo[2,3,- e]pyrazin-1 - y l)bi cy clo [2.2.2]octan-1-yl)cyclopropane- sulfonamide(prepared using E with 4-(tert-butoxycarbonylamino)- bicyclo[2.2.2]octane-1- carboxylic acid [PrimeOrganics], K with cyclopropylsulfonyl chloride, H from Preparation #12,HATU and DIEA, Q with Lawesson's reagent and mercury (II)trifluoroacetate)

D.1.40 1.89 (a) 426 N-(4-(3-(2,3- dihydroxypropyl)-6-tosyl-6H-imidazo[1,5- a]pyrrolo[2,3-e]pyrazin-1-yl)bicyclo[2.2.2]octan-1- yl)cyclopropanesulfonamide (Preparation #17)

D.1.41 1.37 (a) 460 tert-butyl 1-(6-tosyl-6H- imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrrolidin-3- ylcarbamate (Preparation #16)

D.1.42 1.78 (a) 343 3-bromo-1-cyclohexyl-6- tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (Preparation #MM.1)

D.1.43 2.38 (a) 319, 321 (1:1) N-((1S,3S,4R)-3-(3-chloro-6-tosyl-6H-imidazo[1,5- a]pyrrolo[2,3-e]pyrazin-1-yl)-4-ethylcyclopentyl)- cyclopropanesulfonamide (prepared using H fromExample #5, Step C and Preparation #Z.1, HATU and DIEA, Q withLawesson's reagent and mercury (II) trifluroacetate, MM with NCS)

D.1.44* 2.01 (a) 408 N-((1S,3S,4R)-3-(3-bromo-6- tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)- 4-ethylcyclopentyl)-cyclopropanesulfonamide (prepared using H from Example #5, Step C andPreparation #Z.1, HATU and DIEA, Q with Lawesson's reagent and mercury(II) trifluroacetate, MM with NBS)

D.1.45* 2.05 (a) 452, 454 (1:1) N-((3S,5R)-5-ethyl-1-(6-tosyl-6H-imidazo[1,5-a]pyrrolo [2,3-e]pyrazin-1- yl)pyrrolidin-3-yl)cyclopropanesulfonamide, (prepared using E from Preparation #15, Jfrom Example #5, Step C with CDI, OO)

D.1.46* 1.63 (a) 375 N-((3S,5R)-5-methyl-1- (6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3- e]pyrazin-1-yl)pyrrolidin-3-yl)cyclopropanesulfonamide, (prepared using E from Preparation #14, Jfrom Example #5, Step C with CDI, OO)

D.1.47* 1.31 (a) 359 N-((1S,3R,4S)-3-ethyl-4-(7-methyl-6-tosyl-6H-pyrrolo [2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl) cyclo-propanesulfonamide (prepared using Awith Preparation #18 and Preparation #Z.1, B with thionyl chloride andTEA)

D.1.48* 1.74 (a) 389 4-((4-(6-tosyl-6H- imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1- yl)cubanyl)methoxy)benzo- nitrile (prepared using H from(5-tosyl-5H- pyrrolo[2,3-b]pyrazin-2- yl)methanamine hydrochloride(Example #5, Step C) and 4- methoxycarbonylcubane- carboxylic acid[Boron Molecular] with EDC•HCl and DIEA; P with DIBAL-H; II with 4-hydroxybenzonitrile, triphenylphosphine and DIAD; Q with Lawesson'sreagent and mercury (II) trifluoroacetate)

D.1.49 2.05 (a) 392 N-((1S,3R,4S)-3-ethyl- 4-(6-tosyl- 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)-4-methylpiperazine-1- sulfonamide (prepared using ZZ from PreparationBB.1, AAA with 1- methylpiperazine)

D.1.50* 1.32 (a) 433 1-cyclohexyl-2-methyl-6- tosyl-1,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridine (prepared using K.1 fromExample #21, Step E with 4- methylbenzene-1-sulfonyl chloride, L withcyclohexylamine, BBB, G with acetic anhydride and OO)

D.1.51 1.86 (a) 255 1-cyclohexyl-6-tosyl-2- (trifluoromethyl)-1,6-dihydroimidazo [4,5- d]pyrrolo[2,3-b]pyridine (prepared using preparedusing K.1 from Example #21, Step E with 4- methylbenzene-1-sulfonylchloride, L with cyclohexylamine, BBB, G with trifluoroacetic anhydride,DDD with 2,4,6- tripropyl-[1,3,5,2,4,6]tri- oxatriphosphinane 2,4,6-trioxide)

D.1.52 2.37 (a) 309 N-((1S,3R,4S)-3-methyl- 4-(2-methyl-6-tosylimidazo[4,5- d]pyrrolo[2,3-b]pyridin- 1(6H)-yl)cyclopentyl)cyclopropane- sulfonamide (prepared from Preparation #27and Preparation #OOO.1 using L and DIEA, K.1 with TsCl and NaH, BBB, Hwith acetic anhydride, and DDD with POCl₃)

D.1.53* 1.59 (a) 374 1-((1S,2R,4S)-4- (cyclopropylmethoxy)-2-methylcyclopentyl)-6-tosyl- 6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazine (prepared using P from Example #24 Step H and NaBH₄, VV, FFFwith 2- cyclopropylacetaldehyde, Z with NaOH, A with Example #1 Step D,HATU and TEA, B with SOCl₂ and DIEA)

D.1.54 1.73 (a) 312 1-methyl-N-((1S,3R,4S)-3- methyl-4-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3- e]pyrazin-1- yl)cyclopentyl)cyclopropane-1-sulfonamide (prepared from 5-tosyl-5H- pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride (WO2009152133) and(1S,2R,4S)-4-acetamido-2- methylcyclopentane- carboxylic acid [preparedfrom ethyl 4- amino-2-methyl- cyclopentanecarboxylate (WO2009152133)using G, AA [Table 2, Method 3, R_(t) = 6.1 min, or = ND], and Z usingH, OO, BB, and K with 3-chlorophenysulfonyl chloride)

D.1.55* 2.17 (a) 430 N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo [4,3-a]pyrazin-1-yl) cyclopentyl)-2-hydroxyethylamino-1- sulfonamide (Preparation #ZZ.1)

D.1.56* 1.33 (a) 394 N-((1S,3R,4S)-3-ethyl- 4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin- 1-yl)cyclopentyl)-2-methoxyethanesulfonamide (prepared using K from Example #8 Step M and 2-methoxyethane- 1-sulfonyl chloride [Focus Synthesis] with TEA)

D.1.57* 1.53 (b) 393 N-((1S,3R,4S)-3-ethyl- 4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin- 1-yl)cyclopentyl)-2-(1H-1,2,3-triazol-1-yl)ethanesulfon- amide (prepared using K.1 from Example #8Step M and 2-chloroethanesulfonyl chloride with TEA, YY with1H-1,2,3-triazole and DIEA)

D.1.58* 1.45 (b) 430 N-((1S,3R,4S)-3-ethyl-4- (6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin- 1-yl)cyclopentyl)-2-(2H-1,2,3-triazol-2-yl)ethanesulfonamide (prepared using K.1 from Example #8 StepM and 2- chloroethanesulfonyl chloride with TEA, YY with 1H-1,2,3-triazole and DIEA)

D.1.59* 1.58 (b) 430 2-(4,4-difluoropiperidin-1-yl)- N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin- 1-yl)cyclopentyl)ethanesulfon- amide (prepared using K.1 from Example #8Step M and 2-chloroethanesulfonyl chloride with TEA, YY with4,4-difluoropiperidine hydrochloride and DIEA)

D.1.60* 1.76 (b) 482 N-((1S,3R,4S)-3-ethyl- 4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)- 2-morpholinoethanesulfonamide (prepared using K.1 from Example #8 Step Mand 2- chloroethanesulfonyl chloride with TEA, YY with morpholine)

D.1.61* 1.35 (b) 448 (1S,3R,4S)-N-(2-(3,3- difluoropyrrolidin-1-ylsulfonyl)ethyl)-3-ethyl-4- (6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin- 1-yl)cyclopentanamine (prepared usingYY from Preparation #26 and Example #8 Step M with DIEA)

D.1.62* 1.53 (b) 468 (cis)-6-tosyl-1-(5-(3,3,3-trifluoropropylsulfonyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-6H-imidazo[1,5- a]pyrrolo[2,3-e]pyrazine (prepared using K from(cis)- tert-butyl 2,5-diazabicyclo [2.2.1]heptane-2-carboxylate(US2003/225268) and 3,3,3- trifluoropropane-1-sulfonyl chloride(Matrix), E with HCl, J with CDI and (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2- yl)methanamine hydrochloride (Example #5, StepC) with DIEA, OO).

D.1.63 1.85 415 (cis)-6-tosyl-1-(5-(3,3,3- trifluoropropylsulfonyl)hexa-hydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)-6H- imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (prepared using K from (cis)-tert-butyl hexahydropyrrolo[3,4- c]pyrrole-2(1H)-carboxylate and 3,3,3-trifluoropropane-1- sulfonylchloride (Matrix), E with HCl, J with CDI and (5- tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride (Example #5, Step C) with DIEA,OO).

D.1.64 1.80 429 1-(6-fluoro-4-(3,3,3- trifluoropropylsulfonyl)-1,4-diazepan-1-yl)-6-tosyl-6H- imidazo[1,5-a]pyrrolo[2,3- e]pyrazine(prepared using K from tert-butyl 6-fluoro-1,4- diazepane-1-carboxylate(WO2007/126935) and 3,3,3- trifluoropropane-1-sulfonyl chloride(Matrix), E with HCl, J with CDI and (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2- yl)methanamine hydrochloride (Example #5, StepC) with DIEA, OO).

D.1.65 1.86 435 trans-N-(4-methyl-1-(3,3,3-trifluoropropylsulfonyl)piper- idin-3-yl)-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3- e]pyrazin-1-amine (prepared using K fromtrans-tert-butyl 4-methylpiperidin-3- ylcarbamate (WO2009/140320) and3,3,3- trifluoropropane-1-sulfonyl chloride (Matrix), E with HCl, J withCDI and (5-tosyl- 5H-pyrrolo[2,3-b]pyrazin-2- yl)methanaminehydrochloride (Example #5, Step C) with DIEA, OO).

 

D.1.66 1.89 431 N-((1S,3R,4S)-3-ethyl-4- (6-tosyl-6H-pyrrolo[2,3-e][1,2,4] triazolo[4,3-a]pyrazin-1- yl)cyclopentyl)-2-methylpropane-2-sulfonamide (Preparation #28)

D.1.67* 1.76 391 6-tosyl-1-(2-(3,3,3- trifluoropropylsulfonyl)-2,5-diazaspiro[3.5]nonan-5-yl)- 6H-imidazo[1,5- a]pyrrolo[2,3-e]pyrazine(prepared using K from 5- benzyl-2,5-diazaspiro[3.5] nonane(WO2008/60767) and 3,3,3-trifluoropropane-1- sulfonyl chloride (Matrix),Y with Pd(OH)₂, J with CDI and (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride (Example #5, Step C) with DIEA,OO).

D.1.68 2.07 443 6-tosyl-1-((trans)-4-(3,3,3-trifluoropropylsulfonyl)octa- hydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-6H-imidazo[1,5-a]pyrrolo[2,3- e]pyrazine (prepared using K from(trans)-tert-butyl octahydro-1H-pyrrolo[3,2- b]pyridine-1-carboxylate(WO2009/140320) and 3,3,3- trifluoropropane-1-sulfonyl chloride(Matrix), E with HCl, J with CDI and (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2- yl)methanamine hydrochloride (Example #5,Step C) with DIEA, OO).

 

D.1.69 1.94 443 1-(7-methyl-4-(3,3,3- trifluoropropylsulfonyl)-1,4-diazepan-1-yl)-6-tosyl-6H- imidazo[1,5-a]pyrrolo[2,3- e]pyrazine(prepared using K from benzyl 7-methyl-1,4- diazepane-1-carboxylate,Hydrochloric Acid (Wlodarczyk, N.; Gilleron, P.; Millet, R.; Houssin,R.; Henichart, J.-P. Tet. Let., 2007, vol. 48, #14 p. 2583-2586) and3,3,3-trifluoropropane-1- sulfonyl chloride (Matrix), Y with Pd(OH)₂, Jwith CDI and (5-tosyl-5H-pyrrolo[2,3- b]pyrazin-2-yl)methanaminehydrochloride (Example #5, Step C) with DIEA, OO).

D.1.70 1.97 431 6-tosyl-1-(5-(3,3,3- trifluoropropylsulfonyl)-2,5-diazaspiro[3.5]nonan-2-yl)- 6H-imidazo[1,5- a]pyrrolo[2,3-e]pyrazine(prepared using K from tert- butyl 2,5- diazaspiro[3.5]nonane-2-carboxylate (WO2008/60767) and 3,3,3-trifluoropropane-1- sulfonylchloride (Matrix), E with HCl, J with CDI and (5- tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride (Example #5, Step C) with DIEA,OO).

D.1.71 2.03 443 3,3,3-trifluoro-N-(1-(6-tosyl- 6H-imidazo[1,5-a]pyrrolo[2,3- e]pyrazin-1-yl)piperidin-3-yl)propane-1-sulfonamide (prepared using K tert-butyl3-aminopiperidine-1- carboxylate (3B-Scientific Corp.) and 3,3,3-trifluoropropane-1-sulfonyl chloride (Matrix), E with HCl, J with CDIand (5-tosyl- 5H-pyrrolo[2,3-b]pyrazin-2- yl)methanamine hydrochloride(Example #5, Step C) with DIEA, OO).

D.1.72 1.76 417 6-tosyl-1-(2-(3,3,3- trifluoropropylsulfonyl)-2,6-diazabicyclo[3.2.1]octan-6- yl)-6H-imidazo[1,5- a]pyrrolo[2,3-e]pyrazine(prepared using K from benzyl 2,6- diazabicyclo[3.2.1]octane-6-carboxylate (Pharmabridge) and 3,3,3-trifluoropropane-1- sulfonylchloride (Matrix), Y with Pd(OH)₂, J with CDI and(5-tosyl-5H-pyrrolo[2,3- b]pyrazin-2-yl)methanamine hydrochloride(Example #5, Step C) with DIEA, OO).

D.1.73 1.92 429 N-((3R,5R)-1-ethyl-5- (6-tosyl- 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)pyrrolidin-3-yl)cyclopropanesulfonamide (prepared using K with (2R,4R)-1-tert-butyl2-methyl 4-aminopyrrolidine-1,2- dicarboxylate Hydrochloric Acid (AcesysPharmatech Corp) and cylcopropylsulfonylchloride and TEA, Z with NaOH, Awith Example #8 Step M, B, E with HCl, X with acetaldehyde.

D.1.74* 1.32 376 (cis)-tert-butyl 3-ethyl-4-(6- tosyl- 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)pyrrolidine-1- carboxylate(prepared using SSS from N-benzyl-1- methoxy-N- ((trimethylsilyl)meth-yl)methanamine and (Z)-ethyl pent-2- enoate (Lee, R. D.; Kassahun, K.;Abbott, F. S. J. of Pharm. Sci., 1989, vol. 78, #8 p. 667-671), TT, Y,M, A, B, E and K with cyclopropylmethanesulfonyl chloride and TEA

 

D.1.75 1.66 375 N-(4-(3-tosyl-3H- dipyrrolo[1,2- a: 2′,3′-e]pyrazin-8-yl)bicyclo[2.2.2]octan-1- yl)cyclopropanesulfonamide (prepared using IIIfrom 5- tosyl-5H-pyrrolo[2,3- b]pyrazine-2-carbaldehyde (Preparation#12: step B) and diethyl 2-(4- (cyclopropanesulfonamido)bi-cyclo[2.2.2]octan-1-yl)-2- oxoethylphosphonate (Preparation #24), W, Twith Lawesson's reagent).

D.1.76 1.97 385 1-methyl-N-((1S,3R,4S)-3- methyl-4-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3- e]pyrazin-1- yl)cyclopentyl)cyclopropane-1-sulfonamide (prepared from 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride (WO2009152133) and(1S,2R,4S)-4-acetamido-2- methylcyclopentanecarboxylic acid [preparedfrom ethyl 4- amino-2-methyl- cyclopentanecarboxylate (WO2009152133)using G, AA [Table 2, Method 3, R_(t) = 6.1 min, or = ND], and Z] usingH, OO, BB, and K from Preparation #6 and TEA)

D.1.77* 1.87 (a) 374 3,3-difluoro-N-((1S,3R,4S)-3- methyl-4-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3- e]pyrazin-1- yl)cyclopentyl)azetidine-1-sulfonamide (prepared from 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride (WO2009152133) and(1S,2R,4S)-4-acetamido-2- methylcyclopentanecarboxylic acid [preparedfrom ethyl 4- amino-2-methyl- cyclopentanecarboxylate (WO2009152133)using G, AA [Table 2, Method 3, R_(t) = 6.1 min, or = ND], and Z usingH, OO, BB, ZZ and AAA with 3,3- difluoroazetidine hydrochloride and TEA)

D.1.78* 1.99 (a) 411 3,3,3-trifluoro-N- ((1S,3R,4S)-3-methyl-4-(6-tosyl-6H- imidazo[1,5-a]pyrrolo[2,3- e]pyrazin-1-yl)cyclopentyl)propane-1- sulfonamide (prepared from5-tosyl-5H-pyrrolo[2,3- b]pyrazin-2-yl)methanamine hydrochloride(WO2009152133) and (1S,2R,4S)-4-acetamido-2-methylcyclopentanecarboxylic acid [prepared from ethyl 4-amino-2-methyl- cyclopentanecarboxylate (WO2009152133) using G, AA[Table 2, Method 3, R_(t) = 6.1 min, or = ND], and Z using H, OO, BB,and K from 3,3,3-trifluoro-propane- 1-sulfonyl chloride [Matrix] andTEA)

D.1.79* 2.00 (a) 416 3,3-difluoro-N-((1S,3R,4S)-3- methyl-4-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3- e]pyrazin-1- yl)cyclopentyl)pyrrolidine-1-sulfonamide (prepared from 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride (WO2009152133) and(1S,2R,4S)-4-acetamido-2- methylcyclopentanecarboxylic acid [preparedfrom ethyl 4- amino-2-methyl- cyclopentanecarboxylate (WO2009152133)using G, AA [Table 2, Method 3, R_(t) = 6.1 min, or = ND], and Z] usingH, OO, BB, ZZ and AAA with 3,3- difluoropyrrolidine hydrochloride andTEA)

D.1.80* 2.01 (a) 425 (R)-N-((1S,3R,4S)-3-methyl- 4-(6-tosyl-6H-imidazo[1,5- a]pyrrolo[2,3-e]pyrazin-1- yl)cyclopentyl)-2-(trifluoromethyl)pyrrolidine- 1-sulfonamide sulfonamide (Preparation#AAA.1)

D.1.81* 2.16 (a) 457 1-ethyl-N-((1S,3R,4S)-3- ethyl-4-(6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl) cyclopropane-1-sulfonamide (prepared fromExample #8 Step M and Preparation #EEE.1 using K and TEA)

D.1.82* 1.90 (a) 403 1-ethyl-N-((1S,3R,4S)-3- methyl-4-(6-tosyl-6H-imidazo[1,5- a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentyl)cyclopropane- 1-sulfonamide (prepared from5-tosyl-5H-pyrrolo[2,3- b]pyrazin-2-yl)methanamine hydrochloride(WO2009152133) and ((1S,2R,4S)-4-acetamido-2-methylcyclopentanecarboxylic acid [prepared from ethyl 4-amino-2-methyl- cyclopentanecarboxylate (WO2009152133) using G, AA[Table 2, Method 3, R_(t) = 6.1 min, or = ND], and Z] using H, OO, BB,and K using Preparation #EEE.1 and TEA)

D.1.83* 1.96 (a) 388 1-butyl-N-((1S,3R,4S)-3- ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e] [1,2,4]triazolo[4,3-a]pyrazin- 1-yl)cyclopentyl)cyclopropane- 1- sulfonamide (prepared from Example #8Step M and 1- butylcyclopropane-1-sulfonyl chloride [prepared fromPreparation #6 Step A and 1,1,1- trifluoro-2-iodoethane, KHMDS usingKKK, JJJ, and EEE with TEA] using K and TEA)

D.1.84* 2.13 (a) 431 N-((1S,3R,4S)-3-methyl-4- (6-tosylimidazo[4,5-d]pyrrolo[2,3-b]pyridin- 1(6H)- yl)cyclopentyl)cyclopropane- sulfonamide(Preparation #DDD.1)

D.1.85* 1.65 (a) 360 N-((1S,3S,4R)-3-(2- cyclopropyl-6-tosylimidazo[4,5- d]pyrrolo[2,3-b]pyridin- 1(6H)-yl)-4-methylcyclopentyl)cyclo- propanesulfonamide (prepared from Preparation#27 and Preparation #OOO.1 using L and DIEA, K.1 with TsCl and NaH, BBB,H with cyclopropanecarboxylic acid, HATU, and TEA, and DDD with POCl₃)

D.1.86* 1.74 (a) 400 N-((1S,3R,4S)-3-ethyl-4-(6- tosylpyrrolo[2,3-b][1,2,3]triazolo[4,5- d]pyridin-1(6H)- yl)cyclopentyl)cyclo-propanesulfonamide (Preparation #SSSS.1)

D.1.87* 1.82 (a) 375 N-((1S,3R,4S)-3-ethyl-4- (6-tosyl- 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)pentane-2-sulfonamide (prepared using K from Example #8 Step M andpentane-2-sulfonyl chloride)

D.1.88* 1.88 (b) 405 N-((1S,3R,4S)-3-ethyl-4-(6- tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin- 1-yl)cyclopentyl)-3-phenylpropane-1-sulfonamide (prepared using K from Example #8 Step M and3-phenylpropane-1-sulfonyl chloride)

D.1.89* 1.98 (b) 453 N-((1S,3R,4S)-3-ethyl-4-(6- tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin- 1-yl)cyclopentyl)-4,4,4-trifluorobutane-1- sulfonamide (prepared using K from Example #8Step M and 4,4,4-trifluorobutane-1- sulfonyl chloride)

D.1.90* 1.85 (b) 445 2-ethyl-N-((1S,3R,4S)-3- ethyl-4-(6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)cyclopropane- 1-sulfonamide (prepared using K fromExample #8 Step M and 2- ethylcyclopropane-1-sulfonyl chloride)

D.1.91* 1.81 (b) 403 N-((1S,3R,4S)-3-ethyl-4- (6-tosyl- 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)- 2-methylpropane-1-sulfonamide (prepared using K from Example #8 Step M and2-methylpropane-1- sulfonyl chloride)

D.1.92* 1.77 (b) 391 N-((1S,3R,4S)-3-ethyl-4- (6-tosyl- 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)-2-phenylethanesulfonamide (prepared using K from Example #8 Step M and2- phenylethanesulfonyl chloride)

D.1.93* 1.92 (b) 439 1-cyclohexyl-N-((1S,3R,4S)- 3- ethyl-4-(6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)methanesulfon- amide (prepared using K from Example #8Step M and cyclohexylmethanesulfonyl chloride)

D.1.94* 2.04 (b) 431 N-((1S,3R,4S)-3-ethyl-4- (6-tosyl- 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)butane-1- sulfonamide(prepared using K from Example #8 Step M and butane-1-sulfonyl chloride)

D.1.95* 1.78 (b) 391 N-((1S,3R,4S)-3-ethyl-4- (6-tosyl- 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)propane-2-sulfonamide (prepared using K from Example #8 Step M andpropane-2-sulfonyl chloride)

D.1.96* 1.61 (b) 377 N-((1S,3R,4S)-3-ethyl-4- (6-tosyl- 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)-1-phenylmethanesulfonamide (prepared using K from Example #8 Step M andphenylmethanesulfonyl chloride)

D.1.97* 1.82 (b) 425 N-((1S,3R,4S)-3-ethyl-4- (6-tosyl- 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)propane-1-sulfonamide (prepared using K from Example #8 Step M andpropane-1-sulfonyl chloride)

D.1.98* 1.64 (b) 377 N-((1S,3R,4S)-3-ethyl-4- (6-tosyl- 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)- 3-methylbutane-1-sulfonamide (prepared using K from Example #8 Step M and3-methylbutane-1- sulfonyl chloride)

D.1.99* 1.90 (b) 405 N-((1S,3R,4S)-3-ethyl-4- (6-tosyl- 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)- 1,1-difluoromethanesulfonamide (prepared using K from Example #8 Step M anddifluoromethanesulfonyl chloride)

D.1.100* 1.75 (b) 385 4-cyano-N-(1S,3R,4S)-3- ethyl-4-(6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)butane-1- sulfonamide (prepared using K from Example #8Step M and 4-cyanobutane-1-sulfonyl chloride)

D.1.101* 1.56 (b) 416 2-ethoxy-N-((1S,3R,4S)-3- ethyl-4-(6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)ethanesulfon- amide (prepared using K from Example #8Step M and 2- ethoxyethanesulfonyl chloride)

D.1.102* 1.62 (b) 407 N-((1S,3R,4S)-3-ethyl-4- (6-tosyl- 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)-1-(tetrahydrofuran-2- yl)methanesulfonamide (prepared using K fromExample #8 Step M and (tetrahydrofuran-2- yl)methanesulfonyl chloride)

D.1.103* 1.58 (b) 419 N-((1S,3R,4S)-3-ethyl-4- (6-tosyl- 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)- tetrahydro-2H-pyran-4-sulfonamide (prepared using K from Example #8 Step M andtetrahydro-2H-pyran-4- sulfonyl chloride)

D.1.104* 1.50 (b) 419 3-cyano-N-((1S,3R,4S)-3- ethyl-4-(6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)propane-1- sulfonamide (prepared using K from Example #8Step M and 3-cyanopropane-1- sulfonyl chloride)

D.1.105* 1.51 (b) 402 N-((1S,3R,4S)-3-ethyl-4- (6-tosyl- 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)-1-(5-methylisoxazol-3- yl)methanesulfonamide (prepared using K fromExample #8 Step M and (5- methylisoxazol-3- yl)methanesulfonyl chloride)

D.1.106* 1.66 (b) 430 N-((1S,3R,4S)-3-ethyl-4- (6-tosyl- 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)-1-(tetrahydro-2H-pyran-2- yl)methanesulfonamide (prepared using K fromExample #8 Step M and (tetrahydro-2H-pyran-2- yl)methanesulfonylchloride)

D.1.107* 1.73 (b) 433 N-((1S,3R,4S)-3-ethyl-4- (6-tosyl- 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)- 2-(pyridin-2-yl)ethanesulfonamide (prepared using K from Example #8 Step M and 2-(pyridin-2-yl)ethanesulfonyl chloride)

D.1.108* 1.58 (b) 440 1-(2,2-dichlorocyclopropyl)- N-((1S,3R,4S)-3-ethyl-4-(6- tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentyl)methanesulfon- amide (prepared using K fromExample #8 Step M and (2,2- dichlorocyclopropyl)methane- sulfonylchloride)

D.1.109* 1.91 (b) 457 N-((1S,3R,4S)-3-methyl-4-(6- tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)- 3-phenylpropane-1-sulfonamide (prepared using K from Preparation #19.2 and3-phenylpropane-1-sulfonyl chloride)

D.1.110* 1.90 (b) 439 4,4,4-trifluo-N-((1S,3R,4S)-3-methyl-4-(6-tosyl-6H- pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)butane-1- sulfonamide (prepared using K from Preparation#19.2 and 4,4,4-trifluorobutane-1- sulfonyl chloride)

D.1.111* 1.76 (b) 431 2-ethyl-N-((1S,3R,4S)-3- methyl-4-(6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)cyclopropane- 1-sulfonamide (prepared using K fromPreparation #19.2 and 2- ethylcyclopropane-1-sulfonyl chloride)

D.1.112* 1.70 (b) 389 2-methyl-N-((1S,3R,4S)-3- methyl-4-(6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin- 1-yl)cyclopentyl)propane-1-sulfonamide (prepared using K from Preparation #19.2 and2-methylpropane-1- sulfonyl chloride)

D.1.113* 1.67 (b) 377 N-((1S,3R,4S)-3-methyl- 4-(6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)- 2-phenylethanesulfonamide (prepared using Kfrom Preparation #19.2 and 2- phenylethanesulfonyl chloride)

D.1.114* 1.83 (b) 425 N-((1S,3R,4S)-3-methyl- 4-(6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)- yl)cyclopentyl)butane-2- sulfonamide(prepared using K from Preparation #19.2 and 2-(methylsulfonyl)butane)

D.1.115* 1.63 (b) 377 1-cyclohexyl-N- (1S,3R,4S)-3-methyl-4-(6-tosyl-6H- pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)methanesulfon- amide (prepared using K from Preparation#19.2 and cyclohexylmethanesulfonyl chloride)

D.1.116* 1.94 (b) 417 N-((1S,3R,4S)-3-methyl- 4-(6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)butane-1- sulfonamide (prepared using K from Preparation#19.2 and butane-1-sulfonyl chloride)

D.1.117* 1.67 (b) 377 2-methoxy-N-((1S,3R,4S)-3- methyl-4-(6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)ethanesulfon- amide (prepared using K from Preparation#19.2 and 2- methoxyethanesulfonyl chloride)

D.1.118* 1.38 (b) 379 N-((1S,3R,4S)-3-methyl-4-(6- tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)propane-2-sulfonamide (prepared using K from Preparation #19.2 andpropane-2-sulfonyl chloride)

D.1.119* 1.50 (b) 363 N-((1S,3R,4S)-3-methyl-4-(6- tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)-1-phenylmethanesulfonamide (prepared using K from Preparation #19.2 andphenylmethanesulfonyl chloride)

D.1.120* 1.72 (b) 411 N-((1S,3R,4S)-3-methyl-4-(6- tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)propane-1-sulfonamide (prepared using K from Preparation #19.2 andpropane-1-sulfonyl chloride)

D.1.121* 1.53 (b) 363 N-((1S,3R,4S)-3-methyl-4-(6- tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)- 3-methylbutane-1-sulfonamide (prepared using K from Preparation #19.2 and3-methylbutane-1-sulfonyl chloride)

D.1.122* 1.80 (b) 391 N-((1S,3R,4S)-3-methyl-4-(6- tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)-1,1-difluoromethanesulfonamide (prepared using K from Preparation #19.2 anddifluoromethanesulfonyl chloride)

D.1.123* 1.64 (b) 371 4-cyano-N-((1S,3R,4S)- 3-methyl-4-(6-tosyl-6H-pyrrolo[2,3-e] [1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)butane-1- sulfonamide (prepared using K fromPreparation #19.2 and 4-cyanobutane-1-sulfonyl chloride)

D.1.124* 1.45 (b) 402 2-ethoxy-N-((1S,3R,4S)-3- methyl-4-(6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)ethanesulfon- amide (prepared using K from Preparation#19.2 and 2- ethoxyethanesulfonyl chloride)

D.1.125* 1.50 (b) 393 N-((1S,3R,4S)-3-methyl-4-(6- tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)-1-(tetrahydrofuran-2- yl)methanesulfonamide (prepared using K fromPreparation #19.2 and (tetrahydrofuran-2- yl)methanesulfonyl chloride)

D.1.126 1.46 (b) 405 N-((1S,3R,4S)-3-methyl-4-(6- tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)tetrahydro-2H-pyran-4-sulfonamide (prepared using K from Preparation #19.2 andtetrahydro-2H-pyran-4- sulfonyl chloride)

D.1.127* 1.39 (b) 405 3-fluoro-N-((1S,3R,4S)-3- methyl-4-(6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)propane-1- sulfonamide (prepared using K fromPreparation #19.2 and 3-fluoropropane-1-sulfonyl chloride)

D.1.128* 1.48 (b) 381 3-cyano-N-((1S,3R,4S)-3- methyl-4-(6-tosyl-6H-pyrrolo[2,3-e] [1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)propane-1- sulfonamide (prepared using K fromPreparation #19.2 and 3-cyanopropane-1-sulfonyl chloride)

D.1.129* 1.39 (b) 388 N-((1S,3R,4S)-3-methyl-4-(6- tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)-1-(5-methylisoxazol-3- yl)methanesulfonamide (prepared using K fromPreparation #19.2 and (5- methylisoxazol-3- yl)methanesulfonyl chloride)

D.1.130* 1.55 (b) 416 N-((1S,3R,4S)-3-methyl-4-(6- tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)-1-(tetrahydro-2H-pyran-2- yl)methanesulfonamide (prepared using K fromPreparation #19.2 and (tetrahydro-2H-pyran-2- yl)methanesulfonylchloride)

D.1.131* 1.63 (b) 419 N-((1S,3R,4S)-3-methyl-4-(6- tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)- 2-(pyridin-2-yl)ethanesulfonamide (prepared using K from Preparation #19.2 and 2-(pyridin-2-yl)ethanesulfonyl chloride)

D.1.132* 1.47 (b) 426 1-(benzo[d]isoxazol-3-yl)-N-((1S,3R,4S)-3-methyl-4-(6- tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentyl)methane- sulfonamide (prepared using K fromPreparation #19.2 and benzo[d]isoxazol-3- ylmethanesulfonyl chloride)

D.1.133* 1.77 (b) 452 1-(2,2-dichlorocyclopropyl)- N-((1S,3R,4S)-3-methyl-4-(6- tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentyl)methane- sulfonamide (prepared using K fromPreparation #19.2 and (2,2- dichlorocyclopropyl)methane sulfonylchloride)

D.1.134* 1.81 (b) 443 tert-butyl 3-(N-((1S,3R,4S)-3-methyl-4-(6-tosyl-6H- pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)sulfamoyl)azet- idine-1-carboxylate (prepared using Kfrom Preparation #19.2 and tert-butyl 3- (chlorosulfonyl)azetidine-1-carboxylate)

D.1.135* 1.78 (b) 476 (N-((1S,3R,4S)-3- ethyl-4-(6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)-N-(4,4,4- trifluorobutyl)oxetan-3-amine (prepared using X from Example#8 Step M with oxetan-3-one [PharmaBlock R&D], X with 4,4,4-trifluorobutanal [Matrix])

D.1.136* 1.75 (a) 437 (N-((1S,3R,4S)-3-(2-amino-6- tosylimidazo[4,5-d]pyrrolo[2,3-b]pyridin- 1(6H)-yl)-4- ethylcyclopentyl)cyclo-propanesulfonamide (Preparation #RRRR.1)

D.1.137* 1.30 (a) 389 (N-((1S,3R,4S)-3- ethyl-4-(6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)-N-(3,3,3- trifluoropropyl)oxetan-3- amine (prepared using X from Example#8 Step M with oxetan-3-one [PharmaBlock], and X with 3,3,3-trifluoropropanal [Apollo Sci])

D.1.138* 1.91 (b) 423 (3R,4S)-N-cyclopropyl-3- ethyl-4- (6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentane- 1-sulfonamide(prepared using EEE from Preparation #QQQQ.1; K with cyclopropylamine)

D.1.139* 1.53 (b) 375 N-((3R,5R)-1- (2,2-difluoroethyl)-5-(6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)pyrrolidin-3- yl)cyclopropanesulfonamide (prepared usingK from (2R,4R)-1-tert- butyl-4- aminopyrrolidine-1,2- dicarboxylatehydrochloric acid (Acesys Pharmatech Corp) andcylcopropylsulfonylchloride, TEA, Z with NaOH, A with Example #1 Step D,HATU and TEA, B with SOCl₂ and TEA, E with HCl, S with 1,1-difluoro-2-iodoethane)

D.1.140* 1.46 (a) 412 N-((3R,5R)-1-ethyl-5- (6-tosyl- 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)pyrrolidin-3- yl)-N-methylcyclopropanesulfon- amide (prepared using K from (2R,4R)-1-tert-butyl-4- aminopyrrolidine-1,2- dicarboxylate Hydrochloric acid (AcesysPharmatech Corp), d cylcopropylsulfonylchloride and TEA, Z with NaOH, Awith Example #1 Step D, HATU and TEA, B, E with HCl, X withacetaldehyde, S with iodomethane)

D.1.141* 1.44 (a) 390 1-((cis)-1- (cyclopropylsulfonyl)-4-ethylpyrrolidin-3-yl)-6- tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazine (prepared using K with Example #36 Step F andcylcopropylsulfonylchloride (Matrix) and TEA)

 

D.1.142* 1.50 (a) 361 1-((cis)-1-benzyl-4- isopropylpyrrolidin-3-yl)-6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazine (prepared usingA with (Example #1, Step D) and (cis)-1- benzyl-4-isopropylpyrrolidine-3- carboxylic acid hydrochloride (prepared usingSSS with (Z)- ethyl 4-methylpent-2-enoate and N-benzyl-1-methoxy-N-((trimethylsilyl)meth- yl)methanamine (Aldrich)), B with TEA)

 

D.1.143 0.47 (a) 361 N-((1S,3R,4R)-3-ethyl-4- (6-tosyl-3-(trifluoromethyl)-6H- imidazo[1,5-a]pyrrolo[2,3- e]pyrazin-1-yl)cyclopentyl)cyclopropane- sulfonamide (prepared using H withPreparation #32 and Preparation #Z.1, OO)

D.1.144* 2.12 (a) 442 N-((1S,3R,4R)-3-ethyl-4- (6-tosyl-3-(trifluoromethyl)-6H- imidazo[1,5-a]pyrrolo[2,3- e]pyrazin-1-yl)cyclopentyl)cyclopropane- sulfonamide (prepared using H withPreparation #32 and Preparation #Z.1, OO)

D.1.145* 1.59 (a) 418 N-((1S,3R,4S)-3-ethyl-4- (6-tosyl-3-(trifluoromethyl)-6H- imidazo[1,5-a]pyrrolo[2,3- e]pyrazin-1-yl)cyclopentyl)cyclopropane- sulfonamide (prepared using H withPreparation #32 and Preparation #Z.1, OO)

D.1.146* 1.45 (a) 418 N-((1S,3R,4S)-3-methyl-4- (6-tosyl-3-(trifluoromethyl)-6H- imidazo[1,5-a]pyrrolo[2,3- e]pyrazin-1-yl)cyclopentyl)cyclopropane- sulfonamide (prepared using Y from Example#24 Step J, K with cyclopropylsulfonyl chloride (Matrix), H fromPreparation #32 and OO)

D.1.147* 2.03 (a) 428 1-((cis)-4-ethylpyrrolidin- 3-yl)-6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazine•hydrochloride(prepared using K from Example #36, Step F, 3,3,3-trifluoropropane-1-sulfonyl chloride [Matrix] and TEA)

 

D.1.148* 1.86 (a) 417 1-((cis)-4-ethyl-1-(3,3,3-trifluoropropyl)pyrrolidin-3- yl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazine (prepared using X from Example #36,Step F, 3,3,3-trifluoropropanal [Alfa Aesar], sodiumtriacetoxyborohydride and DIEA)

 

D.1.149* 1.54 (a) 353 4-(2-((cis)-3-ethyl-4- (6-tosyl-6H- pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)pyrrolidin-1- yl)ethyl)morpholine(prepared using X from Example #36, Step F, 2- morpholinoacetaldehyde[Matrix], sodium triacetoxyborohydride and DIEA)

 

D.1.150* 1.35 (a) 370 2-cyclopropyl-1-((cis)- 3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)pyrrolidin-1- yl)ethanone (prepared using H from Example#36, Step F, 2-cyclopropylacetic acid, HATU [Novabiochem] and DIEA)

 

D.1.151* 1.54 (a) 339 1-((cis)-4- ethylpyrrolidin-3-yl)-6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazine•hydrochloride(prepared using H from Example #36, Step F, 2- (tetrahydro-2H-pyran-4-yl)acetic acid [Astatech], HATU [Novabiochem] and DIEA)

 

D.1.152 1.54 (a) 383 N-((1S,3R,4S)-3- ethyl-4-(6-tosyl- 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)-3,3-difluorocyclobutane-1- sulfonamide (prepared using K from Example 8,Step M, Preparation #34, and DIEA)

D.1.153 1.75 (a) 425 1-((cis)-4-ethylpyrrolidin- 3-yl)-6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazine•hydrochloride(prepared using K from Example #36, Step F, Preparation #34, and DIEA)

 

D.1.154 1.90 (a) 411 isopropyl (1S,3R,4S)- 3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentylcarbamate sulfonamide (Preparation #35)

D.1.155* 1.74 (b) 357 3-tosyl-8-(2-tosyl-2-azaspiro[3.3]heptan-6-yl)-3H- imidazo[1,2-a]pyrrolo[2,3- e]pyrazine(Preparation #KKKK.1)

D.1.156 1.99 (a) 294 (M − H)⁻ 4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)bicyclo[2.2.2]octan-1- amine(Example #9 Step F)

D.1.157 2.72 (r) 283 8-(piperidin-1-yl)-3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3- e]pyrazine (prepared using S from Example #3,Step E and 1-(bromoacetyl)piperidine [ChemBridge], E with HCl, OO.1)

D.1.158 1.78 (a) 242 8-(2-(4-methylpiperazin-1-yl)pyrimidin-4-yl)-6-tosyl- 6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazine (Preparation #CCCCC.1)

D.1.159 1.00 (a) 336 8-(2-(4-methylpiperazin-1-yl)quinazolin-4-yl)-6-tosyl- 6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazine (prepared using D from Preparation #BBBBB.1 and NaOH, GGG.1with NBS, K.1 with TsCl and NaH, CCCCC with Preparation #40,tetrakis(triphenylphosphine)pal- ladium(0), LiCl, CsF, and CuI

D.1.160 1.16 (a) 386 8-(2-methoxypyridin-4-yl)-6- tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazine (prepared using D from Preparation#BBBBB.1 and NaOH, GGG.1 with NBS, K.1 with TsCl and NaH, CCCCC with 2-methoxy-4- (tributylstannyl)pyridine [Synthonix],tetrakis(triphenylphosphine)pal- ladium(0), LiCl, CsF, and CuI

D.1.161 1.28 (a) 267 8-(1-benzylpyrrolidin-3-yl)-3-tosyl-3H-imidazo[1,2- a]pyrrolo[2,3-e]pyrazine (prepared using R from 1-benzylpyrrolidine-3- carboxylic acid, S from Example #3 Step E, E withTFA, KKKK with PFPAA)

D.1.162 1.40 (b) 317 2-(3-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin- 1-yl)cyclopentylamino)oxetan- 3-yl)acetonitrile (prepared using YYY fromPreparation #BB.1* and 2-(oxetan-3- yliden)acetonitrile (J. Med. Chem,2010, 53(8) 3227- 3246) with Hunig's base)

D.1.163* 1.35 (a) 366 N-((1S,3R,4S)-3-methyl-4- (6-tosyl-2-(trifluoromethyl)imidazo[4,5- d]pyrrolo[2,3-b]pyridin- 1(6H)-yl)cyclopentyl)cyclopropane- sulfonamide (prepared using L fromPreparation #27 and Preparation #OOO.1 and DIEA, K with TsCl and NaH,BBB, CCC with TFAA, DDD with HCl)

D.1.164 1.95 (a) 428 N-(3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo [4,3-a]pyrazin-1-yl)cyclopentyl)-N-(4,4,4- trifluorobutyl)acetamide (prepared using Xfrom Example #8 Step M and 4,4,4-trifluorobutanal [Matrix], CCC withAc₂O)

D.1.165* 1.85 (a) 423 N-((1S,3R,4S)-3-ethyl-4- (6-tosyl- 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)-N-((tetrahydro-2H-pyran-4- yl)methyl)acetamide (prepared using X fromExample #8 Step M and tetrahydro-2H-pyran-4- carbaldehyde [Pharmacore],CCC with Ac₂O)

D.1.166* 1.61 (a) 411 N-(cyclopropylmethyl-N- ((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)acetamide (prepared using X from Example #8 Step M andcyclopropanecarbaldehyde, CCC with Ac₂O)

D.1.167* 1.73 (a) 367 N-((1S,3S,4R)-3-(2- (difluoromethyl)-6-tosylimidazo[4,5- d]pyrrolo[2,3-b]pyridin- 1(6H)-yl)-4-ethylcyclopentyl)cyclopropane- sulfonamide (prepared using H fromExample #23 Step I, difluoroacetic acid, HATU, and TEA, DDD with TPP)

D.1.168 1.76 (a) 424 N-((1S,3R,4S)-3-ethyl-4-(6- tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)-N-methyloxetan-3-amine (prepared using X from Preparation #25 and N-methyloxetan-3-amine [Synthonix])

D.1.169 1.02 (a) 341 (1S,3R,4S)-3-ethyl-N-((3-methyloxetan-3-yl)methyl)-4- (6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentanamine (prepared usingX from Preparation #25 and (3- methyloxetan-3- yl)methanamine[Synthonix])

D.1.170 1.11 (a) 355 N-((1S,3R,4S)-3-ethyl-4-(2-methyl-6-tosylimidazo[4,5- d]pyrrolo[2,3-b]pyridin- 1(6H)-yl)cyclopentyl)cyclopropane- sulfonamide (prepared using CCC fromExample #23 Step I and Ac₂O, DDD with TPP)

D.1.171 1.53 (a) 358 N-(cyclopropylmethyl)- N-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)- 3-methyloxetan-3-amine (prepared using Xfrom Preparation #25 and 3- methyloxetan-3-amine [Synthonix], X usingcyclopropanecarbaldehyde)

D.1.172 1.23 (a) 395 N-(2-cyclopropylethyl)- N-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)- 3-methyloxetan-3-amine (prepared using Xfrom Preparation #25 and 3- methyloxetan-3-amine [Synthonix], X using 2-cyclopropylacetaldehyde [Anichem])

D.1.173 1.40 (a) 409 N-((1S,3R,4S)-3-ethyl-4- (6-tosyl-2-(trifluoromethyl)imidazo[4,5- d]pyrrolo[2,3-b]pyridin- 1(6H)-yl)cyclopentyl)cyclopropane- sulfonamide (prepared using CCC fromExample #23 Step I and TFAA, DDD with HCl)

D.1.174 1.95 (a) 442 3-((1R,3R,4S)-3-ethyl- 4-(6-tosyl- 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyloxy)propane- nitrile(prepared using YYY from Example #41 Step I and acrylonitrile, Z withNaOH, A with Example #1 Step D, HATU and TEA, B with thionyl chlorideand TEA)

D.1.175 1.72 (b) 325

TABLE D.2 Examples prepared using General Procedure D with Na₂CO₃ R_(t)min Example (Table 1, m/z ESI+ Sulfonamide Product # Method) (M + H)⁺(S)-5-(3-((6-tosyl-6H- pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)methyl)pyrrolidin-1- yl)pyrazine-2-carbonitrile (Preparation #L.1)

D.2.1* 1.46 (a) 346 2-(4-cyanophenyl)-N- ((1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)acetamide (prepared using E from Preparation #B.1 withHCl, and H with 4- cyanophenylacetic acid, EDC and DIEA)

D.2.2* 1.20 (c) 386 4-cyano-N-((1S,3R)-3-(6- tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)benzamide (preparedusing E from Preparation #B.1 with HCl, H with 4-cyanobenzoic acid, EDC,and DIEA)

D.2.3* 1.16 (c) 372 3-((1R,3R)-3-(6-tosyl-6H- pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentylamino)benzo- nitrile(prepared using PP with Example #2, Step F, 3- cyanophenylboronic acidand DIEA)

D.2.4* 1.91 (a) 344 3-cyano-N-((1S,3R,4S)-3- ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4] triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)azetidine-1- sulfonamide (prepared using DD with Example#8, Step M, 3-cyanoazetidine- 1-sulfonyl chloride [prepared from CC withazetidine-3-carbonitrile hydrochloride (Astatech) and DIEA] and TEA)

D.2.5* 1.82 (a) 415 3-((1S,3R,4S)-3-methyl-4- (6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentylamino)- benzonitrile(prepared using PP from Preparation #19.2, 3-cyanophenyl boronic acid,and DIEA)

D.2.6* 2.04 (a) 358 5-((1S,3R,4S)-3-methyl-4- (6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentylamino)-pyrazine-2-carbonitrile (prepared using L from Preparation #19.2, 2-chloro-5-cyanopyrazine [ArkPharm], and DIEA)

D.2.7* 1.89 (a) 360 6-((1S,3R,4S)-3-methyl-4- (6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentylamino)-nicotinonitrile (prepared using L from Preparation #19.2, 5-cyano-2-fluoropyridine [Matrix] and DIEA)

D.2.8* 1.81 (a) 359 2-((1S,3R,4S)-3-methyl-4- (6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentylamino)-thiazole-5-carbonitrile (prepared using L from Preparation #19.2, 2-chlorothiazole-5- carbonitrile [ArkPharm] and DIEA)

D.2.9* 1.89 (a) 365 6-((1R,3R,4R)-3-ethyl-4-(6- tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyloxy)nicotino- nitrileand 6-((1S,3S,4S)-3- ethyl-4-(6-tosyl-6H- pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyloxy)- nicotinonitrile(prepared using II from 6- hydroxynicotinonitrile [Asta Tech],Preparation #FF.1, and DEAD)

 

D.2.10 2.01 (b) 374 5-((1S,3R,4S)-3-ethyl-4-(6- tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentylamino)-pyrazine-2-carbonitrile (prepared using L from Example #8, Step M and 2-chloro-5-cyanopyrazine [ArkPharm] and DIEA)

D.2.11* 1.94 (a) 374 1-((1S,3R)-3-(6-tosyl-6H- pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)-1H-pyrrole-3-carbonitrile (Preparation #4)

D.2.12* 1.92 (a) 318 5-((1S,3R,4S)-3-ethyl-4-(6- tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1- yl)cyclopentylamino)pyrazine- 2-carbonitrile(prepared using H from Example #8, Step K, Example #5, Step C, HATU andTEA, Q with Lawesson's reagent and mercury (II) trifluoroacetate, BBwith HCl, L with 2-chloro-5- cyanopyrazine [ArkPharm] and DIEA)

D.2.13* 2.10 (a) 373 5-(((1S,3R)-3-(6-tosyl-6H- pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)methyl-amino)pyrazine-2- carbonitrile (prepared using M from (1R,3S)-3-(aminomethyl)cyclo- pentanecarboxylic acid (AFID), A from Example #1,Step D, HATU and TEA, C with TEA, L with 2-chloro-5-cyanopyrazine[ArkPharm] and DIEA)

D.2.14* 1.79 (a) 360 5-(((1S,3S)-3-(6-tosyl-6H- pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)methyl-amino)pyrazine-2- carbonitrile and 5- (((1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)methyl-amino)pyrazine-2- carbonitrile (prepared using M from (1R,3S)-3-(aminomethyl)cyclo- pentanecarboxylic acid (AFID), H from Example #5,Step C, HATU and TEA, Q with Lawesson's reagent and mercury(II)trifluoroacetate, E with HCl, L with 5- chloropyrazine-2- carbonitrile[ArkPharm] and DIEA)

D.2.15* 1.84 (a) 359 5-(((1S,3S)-3-(6-tosyl-6H- pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)methyl-amino)pyrazine-2- carbonitrile and 5- (((1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)methyl-amino)pyrazine-2- carbonitrile (prepared using M from (1R,3S)-3-(aminomethyl)cyclo- pentanecarboxylic acid (AFID), H from Example #5,Step C, HATU and TEA, Q with Lawesson's reagent and mercury(II)trifluoroacetate, L with 5- chloropyrazine-2- carbonitrile [ArkPharm]and DIEA)

D.2.16* 1.73 (a) 359 6-(cis-3-methyl-4-(6-tosyl- 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentylamino)-nicotinonitrile (prepared using Y from Preparation #46 with Pd(OH)₂ onC, Z with NaOH, M, A from Example #1, Step D, HATU, and TEA, C with TEA,L with 6- fluoronicotinonitrile [Matrix] and DIEA)

 

D.2.17 1.74 (a) 359 5-((cis-3-ethyl-4-(6-tosyl- 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)methoxy)-pyrazine-2-carbonitrile (prepared using P from Preparation #11 with LAH,JJ with 2-chloro-5- cyanopyrazine [ArkPharm], TT with HCl, A fromExample #1, Step D with HATU and TEA, B with TEA)

 

D.2.18 1.81 (a) 407 6-((1S,3R,4S)-3-ethyl-4-(6- tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentylamino)-nicotinonitrile (prepared using L from Example #8, Step M and 6-fluoronicotinonitrile [Matrix] and DIEA)

D.2.19* 2.02 (a) 373 5-((1R,3R)-3-(6-tosyl-6H- pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentylamino)-pyrazine-2-carbonitrile (prepared using L from Example #2, Step F, 5-chloropyrazine-2- carbonitrile[Ark Pharm] and DIEA)

D.2.20* 1.57 (b) 346 5-((1S,3R,4S)-3-methyl-4- (6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1- yl)cyclopentylamino)pyrazine- 2-carbonitrile(prepared using L from Preparation #19.2, 2-chloropyrazine-2-carbonitrile [Ark Pharm] and DIEA)

D.2.21* 1.97 (b) 359 6-((1R,3R,4S)-3-ethyl-4-(6- tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyloxy)- nicotinonitrileand 6- ((1S,3S,4R)-3-ethyl-4-(6- tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyloxy)- nicotinonitrile(prepared using II from 6- hydroxynicotino-nitrile [Asta Tech],Preparation #FF.1 and DEAD)

 

D.2.22 1.99 (b) 374 2-(((1S,3R)-3-(6-tosyl-6H- pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)methylamino)isonicotinonitrile (prepared using A from Example #1, Step D,Preparation #M.1, HATU and TEA, B with TEA; L with 2-fluoroisonicotinonitrile)

D.2.23* 1.69 (a) 359 4-((1R,3R,4S)-3-ethyl-4-(6- tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1- yl)cyclopentyloxy)benzo- nitrile (preparedfrom prepared from 5-tosyl-5H- pyrrolo[2,3-b]pyrazin-2- yl)methanaminehydrochloride (W2009152133) and Preparation #GG.1 using HH with TMA andDIEA, II with 4-cyanophenol, DEAD, PPh₃, and TEA, and Q with Lawesson'sreagent and and mercury (II) trifluoroacetate)

D.2.24 2.28 (a) 372 N-(cyanomethyl)-N- ((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)cyclopropane- sulfonamide (prepared using S.1 from N-((1S,3R,4S)-3-ethyl-4-(6- tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentyl)cyclo- propanesulfonamide [WO2009152133A1]and 2-iodoacetonitrile)

D.2.25* 1.74 (a) 414 (1S,3R,4S)-N-(2- cyclopeopylethyl)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-N-(2,2,2- trifluoroethyl)cyclopentamine (prepared usingX from Preparation #25 with 2,2,2-trifluoroethanamine, X with 2-cyclopropylacetaldehyde [Anichem])

D.2.26* 2.49 (a) 421 (1S,3R,4S)-N- (cyclopropylmethyl)-3-ethyl-4-(6-tosyl-6H- pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-N-(2,2,2- trifluoroethyl)cyclopentanamine (preparedusing X from Preparation #25 with 2,2,2-trifluoroethanamine, X withcyclopropanecarbaldehyde)

D.2.27* 2.31 (a) 407 N-((1S,3R,4S)-3-ethyl-4-(6- tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)cyclopropane-sulfonamide (prepared using K from Example #8, Step M andcyclopropanesulfonyl chloride; YYY from acrylonitrile with DBU)

D.2.28* 1.70 (b) 428 (1S,3R,4S)-3-ethyl-4-(6- tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentanamine (prepared usingK from Example #8, Step M and 3- fluoropropane-1-sulfonyl chloride[Hande]

D.2.29* 1.59 (b) 395 1-((cis)-4-ethylpyrrolidin-3-yl)-6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazine ·hydrochloride (prepared using L from Example #36, Step F, 6-fluoronicotinonitrile [Matrix], and TEA)

 

D.2.30 1.81 (a) 359 1-((cis)-4-ethylpyrrolidin-3-yl)-6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazine ·hydrochloride (prepared using X from Example #36, Step F, 4-formylbenzonitrile, sodium triacetoxyborohydride and DIEA)

 

D.2.31 1.53 (a) 372 1-((cis)-4-ethylpyrrolidin-3-yl)-6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazine ·hydrochloride (prepared using H from Example #36, Step F, 2- cyanoaceticacid, HATU [Novabiochem] and DIEA)

 

D.2.32 1.49 (a) 324 1-((cis)-4-ethylpyrrolidin-3-yl)-6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazine ·hydrochloride (prepared using YYY from Example #36, Step F, 2-(oxetan-3- ylidene)acetonitrile [J. Med. Chem, 2010, 53, 3227-3246], andDIEA)

 

D.2.33 1.55 (a) 352 (1S,3R,4S)-3-ethyl-4-(6H- pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl phenylcarbamate(prepared using WWW from Example #42 Step N and phenylamine)

D.2.34* 2.04 (b) 391

TABLE D.3 Examples prepared using General Procedure D with Na₂CO₃followed by NaOH R_(t) min (Table 1, m/z ESI+ Sulfonamide Product Ex #Method) (M + H)⁺ 3-(cyclopropylmethylamino)-4-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H- pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)- cyclobut-3-ene-1,2-dione (preparedusing TTTT from Preparation #29 and cyclopropylmethanamine)

D.3.1* 1.71 (a) 420 3-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentylamino)-4-(oxetan-3-ylamino)cyclobnut-3-ene-1,2- dione (prepared using TTTT fromPreparation #29 and oxetan-3-amine [Synthonix])

D.3.2* 1.55 (a) 422 3-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentylamino)-4-(3,3,3-trifluoropropylamino)cyclobut-3- ene-1,2-dione (Preparation#TTTT.1)

D.3.3* 1.58 (a) 462 3-(cyclopropylamino)-4-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)cyclobut-3-ene- 1,2-dione (prepared using TTTT fromPreparation #29 and cyclopropylamine)

D.3.4* 1.65 (a) 406

General Procedure E: Acidic Cleavage of a Boc-Protected Amine

To a solution of a Boc-protected amine (preferably 1 equiv) in anorganic solvent (such as DCM, 1,4-dioxane, or MeOH) is added TFA or HCl(preferably 4 N HCl in 1,4-dioxane, 2-35 equiv, preferably 2-15 equiv).The reaction is stirred at about 20-100° C. (preferably ambienttemperature to about 60° C.) for about 1-24 h (preferably about 1-6 h).In any case where an additional acid labile group is present (forexample, a t-butyl ester), this group may also be cleaved during thereaction. Optionally, additional TFA or HCl (preferably 4 N HCl in1,4-dioxane solution, 2-35 equiv, preferably 2-15 equiv) may be added tothe reaction mixture in cases where the reaction does not proceed tocompletion as monitored by TLC, LC/MS, or HPLC. Once the reaction hasproceeded to an acceptable level, the reaction mixture can be concd invacuo to provide the amine as a salt. Alternatively, the reaction may bepartitioned between an organic solvent (such as EtOAc, DCM or1,4-dioxane) and an aqueous base (such as saturated aqueous NaHCO₃ orsaturated aqueous Na₂CO₃, preferably saturated aqueous NaHCO₃). Theaqueous layer can be optionally extracted with additional organicsolvent such as EtOAc or DCM. The combined organic layers may optionallybe washed with brine, dried over anhydrous Na₂SO₄ or MgSO₄, thendecanted or filtered, prior to concentrating under reduced pressure togive the target compound.

Preparation #E.1N-((3S,5R)-5-ethylpyrrolidin-3-yl)cyclopropanesulfonamide hydrochloride

To a solution of (2R,4S)-tert-butyl4-(cyclopropanesulfonamido)-2-ethylpyrrolidine-1-carboxylate (0.95 g,2.98 mmol, Preparation #15) in 1,4-dioxane (7.5 mL) was added HCl (4 Nin 1,4-dioxane, 7.46 mL, 29.8 mmol). The reaction mixture was heated toabout 60° C. After about 4 h, the reaction mixture was cooled to ambienttemperature and concd in vacuo to provide crudeN-((3S,5R)-5-ethylpyrrolidin-3-yl)cyclopropanesulfonamide hydrochloride(0.38 g, 50%) as a brown residue: LC/MS (Table 1, Method a) R_(t)=0.63min; MS m/z: 219 (M+H)⁺.

TABLE E.1 Examples prepared using General Procedure E with HCl R_(t) min(Table 1, m/z ESI+ Boc-protected Amine Product Ex # Method) (M + H)⁺(R)-tert-butyl 3-((3R,4R)-3-(6H- imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidine-1- carbonyl)morpholine-4-carboxylate (preparedusing H from Example #5, Step J and (R)-4-(tert-butoxycarbonyl)morpholine-3- carboxylic acid [Tyger] with EDC · HCl andDIEA)

E.1.1* 1.16 (b) 369 tert-butyl 2-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-ylamino)-2- oxoethylcarbamate (prepared usingH from Preparation #OO.1.1, tert- butoxycarbonylaminoacetic acid [TCI],HATU and TEA, D with NaOH)

E.1.2 1.72 (r) 231 tert-butyl 3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-ylamino)-3- oxopropylcarbamate (prepared usingH from Preparation #OO.1.1, 3-tert- butoxycarbonylaminopropionic acid,HATU and TEA, D with NaOH)

E.1.3 2.09 (r) 245 tert-butyl 4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8- carbonyl)piperazine-1-carboxylate (preparedusing D from Preparation #YYYY.1 and NaOH, H with piperidin-4-yl-carbamic acid tert-buyl ester [Tyger], EDC, HOBt, and TEA)

E.1.4 2.75 (r) 271 tert-butyl 1-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8- carbonyl)piperidin-4-ylcarbamate (preparedusing D from Preparation #YYYY.1 and NaOH, H withpiperazine-1-carboxylic acid tert-butyl ester, EDC, HOBt, and TEA)

E.1.5 2.81 (r) 285 tert-butyl 4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-7- carbonyl)piperazine-1-carboxylate (preparedusing D from Preparation #37 and NaOH, H with piperazine-1- carboxylicacid tert-buyl ester, EDC, HOBt, and TEA)

E.1.6 2.68 (r) 271 tert-buyl (trans-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-8-carboxamido)cyclohexyl)methylcarbamate (Preparation #LL.1.1)

E.1.7 0.74 (a) 314 tert-butyl (trans-4-((6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-8-yl)methylamino)cyclohexyl)methylcarbamate (Preparation #X.1.1)

E.1.8 2.66 (r) 300 tert-butyl (trans-4-((6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)methyl)cyclohexyl)methylcarbamate(Preparation #ZZZZ.1)

E.1.9 1.01 (a) 285 t-butyl 2-(4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidin- 1-yl)ethylcarbamate (preparedusing R from 1-(benzyloxycarbonyl)piperidine- 4-carboxylic acid(Matrix), S from Example #3 Step E, E with TFA, KKKK with PFPAA, D withNaOH, F, X with t-butyl 2-oxoethylcarbamate)

E.1.10 2.28 (r) 285 tert-butyl 4-((3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1- yl)methyl)piperidine-1-carboxylate (preparedusing XX from Preparation #XXXX.1)

E.1.11 1.30 (a) 256

General Procedure E.1: Acidic Cleavage of a Boc-Protected Amine

To a solution of a Boc-protected amine (preferably 1 equiv) in anorganic solvent (such as DCM, 1,4-dioxane, MeOH, or THF) is added anacid (such as TFA, HCl, or H₃PO₄ (preferably H₃PO₄, 1-50 equiv,preferably 5-10 equiv). The reaction is stirred at about 20-100° C.(preferably ambient temperature to about 65° C.) for about 1-24 h(preferably about 1-6 h). In any case where an additional acid labilegroup is present (for example, a t-butyl ester), this group may also becleaved during the reaction. Optionally, additional TFA, HCl, or H₃PO₄may be added to the reaction mixture in cases where the reaction doesnot proceed to completion as monitored by TLC, LC/MS, or HPLC. Once thereaction has proceeded to an acceptable level, the reaction mixture canbe concd in vacuo to provide the amine as a salt. Alternatively, thereaction may be cooled to about −10-25° C. before the addition of anaqueous base (such as saturated aqueous NaHCO₃, saturated aqueousNa₂CO₃, or aqueous K₃PO₄, preferably aqueous K₃PO₄) and optionallypartitioned between an organic solvent (such as EtOAc, DCM, THF, or1,4-dioxane). The aqueous layer can be optionally extracted withadditional organic solvent such as EtOAc or DCM. The combined organiclayers may optionally be washed with brine, dried over anhydrous Na₂SO₄or MgSO₄, then decanted or filtered, prior to concentrating underreduced pressure to give the target compound.

Preparation #E.1.1 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-amine

To a solution of tert-butyl5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (12.35 g, 31.8 mmol,Example #3 Step E) in THF (35 mL) was added H₃PO₄ (20.16 mL, 350 mmol).The reaction mixture was heated to about 65° C. After about 90 min, thereaction mixture was cooled to about 0° C. and a solution of K₃PO₄ (29.0mL, 350 mmol) in water (100 mL) was added. A white precipitate wasremoved by filtration. The organic layer was separated, dried overanhydrous MgSO₄, and concd in vacuo to provide crude5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-amine (8.58 g, 94%) as a tan solid:LC/MS (Table 1, Method a) R_(t)=1.85 min; MS m/z: 289 (M+H)⁺.

General Procedure F: Deprotection of a Cbz Protected Amine Using HBr inAcOH

To a Cbz protected amine (preferably 1 equiv) is added HBr in AcOH(40-400 equiv, preferably 70-90 equiv of 33% HBr in AcOH) at about 0° C.to 40° C. (preferably at ambient temperature) and the mixture is stirredat this temperature for about 5-45 min (preferably about 10 min). Theprecipitate is collected by filtration and extensively washed with anorganic solvent such as Et₂O, EtOAc, 1,4-dioxane, THF or MeCN(preferably EtOAc or MeCN) to yield the target compound.

Illustration of General Procedure F Preparation #F.14-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)bicyclo[2.2.2]octan-1-aminehydrobromide

Benzyl4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)bicyclo[2.2.2]octan-1-ylcarbamate(0.22 g, 0.529 mmol, prepared using Z from Preparation #N.1 and NaOH, Rwith diazomethane, S from Example #3, Step E, T with Lawesson's reagentand D with NaOH) was dissolved in HBr (33% in AcOH, 10 mL) and themixture was stirred for about 10 min at ambient temperature. Thereaction was then diluted with EtOAc (30 mL) and the precipitate wascollected by filtration, extensively washed with MeCN and dried to yield4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)bicyclo[2.2.2]octan-1-aminehydrobromide (0.16 g, 83%) as a yellow solid: LC/MS (Table 1, Method a)R_(t)=1.67 min; MS m/z 282 (M+H)⁺.

TABLE F.1 Examples prepared using General Procedure F with HBr in AcOHR_(t) min (Table 1, m/z ESI+ Cbz-protected Amine Product Ex # Method)(M + H)⁺ benzyl -4-(3H-imidazo[1,2- a]pyrrolo[2,3-e]pyrazin-8-yl)cyclohexylcarbamate (prepared using N from (cis)-4-aminocyclohexanecarboxylic acid with benzyl 2,5-dioxopyrrolidin-1-ylcarbonate and Na₂CO₃, R with (trimethylsilyl)diazomethane, S withExample#3 Step E, E with HCl, T with Lawesson's reagent, D with NaOH)

F.1.1 0.48 and 0.69 (a) 256 benzyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8- yl)cyclohexylcarbamate (prepared using N from(cis)-4- aminocyclohexanecarboxylic acid with benzyl2,5-dioxopyrrolidin-1-yl carbonate and Na₂CO₃, R with(trimethylsilyl)diazomethane, S with Example#3 Step E, E with HCl, Twith Lawesson's reagent, D with NaOH)

F.1.2 2.77 (r) 256 benzyl 3-(3H-imidazo[1,2- a]pyrrolo[2,3-e]pyrazin-8-yl)pyrrolidine-1-carboxylate (prepared using R from 1-(benzyloxycarbonyl)pyrrolidine-3- carboxylic acid (Astatech), S fromExample #3 Step E, E with TFA, KKKK with PFPAA)

F.1.3 2.83 (r) 228 benzyl 4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidine- 1-carboxylate (prepared using Rfrom 1- (benzyloxycarbonyl)piperidine-4- carboxylic acid (Matrix), Sfrom Example #3 Step E, E with TFA, KKKK with PFPAA)

F.1.4 2.82 (r) 242

General Procedure F.1: Deprotection of a Cbz Protected Amine Using HBrin AcOH

To a Cbz protected amine (preferably 1 equiv) is added HBr in aceticacid (5-400 equiv, 33% HBr in AcOH) at about 0° C. to 40° C. (preferablyat ambient temperature) and the mixture is stirred at this temperaturefor about 0.5-5 h (preferably about 1 h). The reaction is worked upusing one of the following methods. Method 1: The precipitate iscollected by filtration and extensively washed with an organic solventsuch as Et₂O, EtOAc, 1,4-dioxane, THF or MeCN (preferably EtOAc or MeCN)to yield the target compound. Method 2: The reaction mixture is dilutedwith water and a suitable organic solvent (such as Et₂O). The layers arestirred for short period and the organic layer is decanted. This isrepeated (3-10×) and the organic layer is discarded. The aqueous layeris basified with an aqueous base (such as saturated aqueous NaHCO₃ orsaturated aqueous Na₂CO₃, preferably saturated aqueous NaHCO₃) andextracted with a suitable organic solvent (such as EtOAc, DCM or Et₂O).The combined organic layers may optionally be washed with brine andconcd in vacuo or dried over anhydrous Na₂SO₄ or MgSO₄ and then decantedor filtered prior to concentrating under reduced pressure to give thetarget compound.

Illustration of General Procedure F.1 Preparation #F.1.18-((cis)-4-ethylpyrrolidin-3-yl)-3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine

To a solution of (cis)-benzyl3-ethyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)pyrrolidine-1-carboxylate(0.838 g, 1.541 mmol, prepared using E from Example #36 Step D with TFA,N, R, S.1 with Example #3 Step E, and T with Lawesson's reagent) wasadded a solution of HBr (2.50 mL, 15.19 mmol, 33% in acetic acid). Thereaction mixture was stirred at ambient temperature for about 1 h. Thereaction was diluted with Et₂O (50 mL) and water (20 mL). The layerswere stirred for about 3 min and the organic layer was decanted then theprocedure was repeated 5 times. The aqueous layer was cooled to about 0°C. was basified with saturated aqueous NaHCO₃ solution (10 mL) to aboutpH 7. The aqueous layer was extracted with EtOAc (3×50 mL), combined,and dried over anhydrous Na₂SO₄, filtered and concd to give a brownsolid. The solid was dissolved in DCM (50 mL) and washed with water(3×20 mL), dried over anhydrous Na₂SO₄, filtered and coned to afford8-((cis)-4-ethylpyrrolidin-3-yl)-3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine(0.453, 61%) as a brown residue: LC/MS (Table 1, Method a) R_(t)=1.73min; MS m/z: 410 (M+H)⁺.

General Procedure G: Formation of an Acetamide

To a solution of amine (preferably 1 equiv) in pyridine (5-25 equiv,preferably 10 equiv) at about 0-25° C. (preferably about 0° C.) is addedAc₂O (2-10 equiv, preferably 5 equiv). If the reaction is cooled,stirring is continued at the lower temperature for about 5-30 min(preferably 10-15 min) and then warmed to ambient temperature. Afterabout 1-24 h (preferably 2-16 h), the reaction is concd under reducedpressure and partitioned between an organic solvent such as EtOAc or DCM(preferably EtOAc) and aqueous acid such as aqueous HCl (1-6 N,preferably 1 N). The layers are separated and the organic layer isoptionally washed with aqueous acid such as aqueous HCl (1-6 N,preferably 1 N), aqueous base such as aqueous NaHCO₃ or aqueous Na₂CO₃(preferably saturated aqueous NaHCO₃), and brine. The organic layer isthen dried over anhydrous MgSO₄, filtered through a pad of Florisil®while washing with additional organic solvent such as EtOAc or DCM(preferably EtOAc), and concd under reduced pressure.

Illustration of General Procedure G Preparation #G.1* (1S,2R,4S)-ethyl4-acetamido-2-ethylcyclopentanecarboxylate

A solution of ethyl 4-amino-2-ethylcyclopentanecarboxylate (49.0 g, 264mmol, Example #8, Step I) in pyridine (214 mL, 2645 mmol) was cooled toabout 0° C. Ac₂O (125 mL, 1322 mmol) was added and stirring wascontinued at about 0° C. for about 15 min. The resulting solution waswarmed to ambient temperature and stirred for about 12 h. The reactionwas concd under reduced pressure and EtOAc (500 mL) and aqueous HCl (1N, 200 mL) were added. The layers were separated and the organic layerwas washed with aqueous HCl (1 N, 200 mL), saturated aqueous NaHCO₃(2×200 mL) and brine (150 mL), dried over anhydrous MgSO₄, filteredthrough a pad of Florisil® while washing with EtOAc (600 mL), and concdunder reduced pressure to give an off-white solid (52 g) that waspurified by using General Procedure AA (Table 2, Method 24, R_(t)=8.2min, or =positive) to give (1S,2R,4S)-ethyl4-acetamido-2-ethylcyclopentanecarboxylate (20.3 g, 34%): LC/MS (Table1, Method a) R_(t)=1.82 min; MS m/z: 228 (M+H)⁺.

TABLE G.1 Examples prepared using General Procedure G R_(t) min m/z(Table 1, ESI+ Amine Product Ex. # Method) (M + H)⁺N-((3R,5R)-5-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)pyrrolidin-3- yl)cyclopropanesulfonamide(prepared using K from (2R,4R)-1-tert-butyl-4-aminopyrrolidine-1,2-dicarboxylate hydrochloric acid (Acesys PharmatechCorp) and cylcopropylsulfonylchloride, TEA, Z with NaOH, A with HATU andTEA, B with SOCl₂ and TEA, E with HCl.

G.1.1* 1.13 390General Procedure H: Formation of an Amide from a Carboxylic Acid and anAmine

To a solution or suspension of a carboxylic acid (1-5 equiv, preferably1.0 equiv) and an amine or an amine salt (1-5 equiv, preferably 1 equiv)in an organic solvent (such as DCM, DCE, THF, or 1,4-dioxane, preferablyDCM) is added a peptide coupling reagent (such as BOP-Cl, IBCF, HATU, orEDC.HCl, preferably HATU, 1-10 equiv, preferably 1-1.5 equiv), a base(such as TEA, DIEA, or pyridine, preferably DIEA, 0-20 equiv, preferably3 equiv). The reaction mixture is then stirred at ambient temperaturefor about 15 min to 24 h (preferably about 45 min-16 h). The reactionmixture is then worked up using one of the following methods. Method 1:The reaction mixture is diluted with water or saturated aqueous NaHCO₃.The layers are separated. The aqueous layer is optionally extracted withadditional organic solvent such as EtOAc or DCM. The organic layer is(or combined layers are) optionally washed with water, saturated aqueousNaHCO₃ and/or brine, dried over anhydrous MgSO₄ or Na₂SO₄, filtered ordecanted, and concd under reduced pressure. Method 2: The crude reactionmixture is filtered through a pad of silica gel, washing with a suitablesolvent (such as EtOAc, MeOH, or DCM, preferably MeOH), and concd underreduced pressure. Method 3: The crude reaction mixture is directlypurified by chromatography without a work up.

Illustration of General Procedure H Preparation #H.1* (3R,4R)-tert-butyl4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)piperidine-1-carboxylate

To a slurry of (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanaminehydrochloride (34.0 g, 100 mmol, Example #5, Step C),(3R,4R)-1-(tert-butoxycarbonyl)-4-methylpiperidine-3-carboxylic acid(24.43 g, 100 mmol, Example #5, Step F) and HATU (38.2 g, 100 mmol) inDCM (700 mL) was added DIEA (52.6 mL, 301 mmol). The reaction wasstirred at ambient temperature for about 45 min. The reaction was washedwith saturated aqueous NaHCO₃ (300 mL). The organic layer was separated,dried over anhydrous Na₂SO₄, filtered, and concd in vacuo. The resultingresidue was purified by chromatography on silica gel (330 g) using33-100% EtOAc in heptanes to give(3R,4R)-tert-butyl-4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)-piperidine-1-carboxylate(53 g, 96%) as a pale-yellow foam: LC/MS (Table 1, Method b) R_(t)=2.40min; MS m/z: 528 (M+H)⁺.

TABLE H.1 Examples prepared from1-((3R,4R)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazinehydrochloride (Example #5, Step J) using General Procedure H withEDC•HCl and DIEA R_(t) min m/z (Table 1, ESI+ Carboxylic Acid ProductExample # Method) (M + H)⁺ 4,4- difluorocyclohexane- carboxylic acid

H.1.1*  1.82 (b) 402 3,3,3-trifluoropropanoic acid

H.1.2*  1.68 (b) 366 3-hydroxy-3- methylbutanoic acid (Fluka)

H.1.3*  1.49 (b) 356 2-methoxyacetic acid

H.1.4*  1.39 (b) 328 3-methoxypropanoic acid

H.1.5*  1.44 (b) 342 pent-4-ynoic acid (Fluka)

H.1.6*  1.59 (b) 336 2-(4-chlorophenyl)acetic acid

H.1.7*  1.90 (b) 408 2-(3-chlorophenyl)acetic acid

H.1.8*  1.91 (b) 408 4-cyanobenzoic acid

H.1.9*  1.68 (b) 385 3-(3-chloroisoxazol-5- yl)propanoic acid (Matrix)

H.1.10* 1.78 (b) 413 2-(3-cyanophenyl)acetic acid

H.1.11* 1.71 (b) 399 2-(4-cyanophenyl)acetic acid

H.1.12* 1.70 (b) 399 2-(1H-pyrrol-2-yl)acetic acid (Tyger)

H.1.13* 1.62 (b) 363 2-(pyrazin-2-yl)acetic acid (Astatech)

H.1.14* 1.37 (b) 376 2-(tetrahydro-2H-pyran-4- yl)acetic acid (Astatech)

H.1.15* 1.49 (b) 382 2-(pyrimidin-2-yl)acetic acid (Caymen Chemical)

H.1.16* 1.56 (b) 376 3-acetamidopropanoic acid

H.1.17* 1.29 (b) 369 tetrahydrofuran-2- carboxylic acid

H.1.18* 1.45 (b) 354 tetrahydrofuran-3- carboxylic acid

H.1.19* 1.43 (b) 354 3- methoxycyclohexane- carboxylic acid

H.1.20* 1.62, 1.69 (b) 396 3,3- difluorocyclobutane- carboxylic acid(Waterstone)

H.1.21* 1.75 (b) 374 4,4,4-trifluorobutanoic acid (Matrix)

H.1.22* 1.78 (b) 380 tetrahydro-2H-pyran-4- carboxylic acid (Matrix)

H.1.23* 1.75 (b) 368 tetrahydro-2H-pyran-3- carboxylic acid (Chem Impex)

H.1.24* 1.74 (b) 368 3-cyanopropanoic acid (Tyger)

H.1.25* 1.65 (b) 337 tetrahydro-2H-pyran-2- carboxylic acid (AcellaChembio Co.)

H.1.26* 1.76 (b) 368 3- (methylsulfonyl)propanoic acid (Enamine)

H.1.27* 1.36 (b) 390 1,4-dioxane-2-carboxylic acid (Enamine)

H.1.28* 1.41 (b) 370 tetrahydrothiophene-3- carboxylic acid-1,1-dioxide

H.1.29* 1.41 (b) 402 1-methylpyrrolidine-3- carboxylic acid (Chembridge)

H.1.30* 1.18 (b) 367 1-methylpiperidine-4- carboxylic acid (Astatech)

H.1.31* 1.19 (b) 381

TABLE H.2 Examples prepared from1-((3R,4R)-4-methylpiperidin-3-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine hydrochloride (prepared using A from Example #1, Step Dand Example #5, Step F, HATU and DIEA; B with DIEA; D with NaOH; E withHCl) using General Procedure H with EDC•HCl and DIEA R_(t) min m/z(Table 1, ESI+ Carboxylic Acid Product Example # Method) (M + H)⁺2-cyanoacetic acid

H.2.1* 1.23 (b) 324

TABLE H.3 Examples prepared from1-(cis)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazinehydrochloride (prepared using D from Preparation #Q.1 with NaOH, and Ewith 4 N HCl in 1,4-dioxane) using General Procedure H with HATU andDIEA R_(t) min m/z (Table 1, ESI+ Carboxylic Acid Product Example #Method) (M + H)⁺ 2,4-difluorobenzoic acid

H.3.1  1.79 (b) 396 4-(trifluoromethyl) benzoic acid

H.3.2  1.96 (b) 428 nicotinic acid

H.3.3  1.41 (b) 361 3-(trifluoromethyl) benzoic acid

H.3.4  1.97 (b) 428 pyrazine-2- carboxylic acid

H.3.5  1.40 (b) 362 pyrimidine-5- carboxylic acid [Frontier Scientific]

H.3.6  1.37 (b) 362 2-cyclopropylacetic acid [Lancaster]

H.3.7  1.62 (b) 338 benzoic acid

H.3.8  1.69 (b) 360 2-cyclobutylacetic acid [Beta Pharmaceuticals]

H.3.9  1.78 (b) 352 3- cyclobutylpropanoic acid [ChemBridge]

H.3.10 1.91 (b) 366 1H-pyrazole-4- carboxylic acid

H.3.11 1.32 (b) 350 1H-pyrazole-3- carboxylic acid [Oakwood]

H.3.12 1.34 (b) 350 propionic acid

H.3.13 1.49 (b) 312 1- cyanocyclopropane carboxylic acid

H.3.14 1.60 (b) 349 1-methyl-1H- pyrazole-4- carboxylic acid

H.3.15 1.37 (b) 364 isonicotinic acid

H.3.16 1.44 (b) 361 2-(3-methylisoxazol- 5-yl)acetic acid

H.3.17 1.52 (b) 379 2-(2,4- difluorophenyl) acetic acid

H.3.18 1.84 (b) 410 isoxazole-5- carboxylic acid

H.3.19 1.52 (b) 351

TABLE H.4 Examples prepared from(R)-1-(piperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e] pyrazinehydrochloride (Example #6, Step H) using General Procedure H withEDC•HCl and DIEA R_(t) min m/z (Table 1, ESI+ Carboxylic Acid ProductExample # Method) (M + H)⁺ 3,3- difluorocyclobutanecarboxylic acid(Waterstone)

H.4.1* 1.86 (b) 360

TABLE H.5 Examples prepared from cyclopropanamine (Aldrich) usingGeneral Procedure H with HATU and TEA R_(t) min m/z (Table 1, ESI+Carboxylic Acid Product Example # Method a) (M + H)⁺2-((1S,3R,4S)-3-ethyl-4- (6H-pyrrolo[2,3-e] [1,2,4]triazolo[4,3-a]pyrazin-1-yl) cyclopentyl)acetic acid (Example W.1.2)

H.5.1 1.45 353General Procedure I: Formation of a Urea from an Amine and a CarbamoylChloride

To a flask containing an amine or an amine salt (1 equiv) in an organicsolvent (such as THF or 1,4-dioxane, preferably THF) is added a base(such as DIEA or TEA, preferably TEA [3-5 equiv, preferably 4 equiv])and stirred at ambient temperature for about 0-30 min (preferably about5 min) then added a carbamoyl chloride (0.5-2 equiv, preferably 0.75equiv). The mixture is stirred at about 0-90° C. (preferably about 45°C.) for about 2-24 h (preferably about 18 h). The reaction mixture isallowed to reach ambient temperature. The organic solvent is optionallyremoved under reduced pressure. The crude material can be partitionedbetween an organic solvent (such as EtOAc or DCM) and water, an aqueousbase (such as saturated aqueous NaHCO₃) or brine. The layers areseparated and the organic layer is optionally washed with water, anaqueous base (such as saturated aqueous NaHCO₃) or brine, dried overanhydrous Na₂SO₄ or MgSO₄, filtered, and concd under reduced pressure togive the target compound.

Illustration of General Procedure I Example #I.1.1*((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)(piperidin-1-yl)methanone

A round bottom flask was charged with1-((3R,4R)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazinehydrochloride (0.050 g, 0.17 mmol, Example #5, Step J), TEA (0.10 mL,0.69 mmol) in THF (1.6 mL). The reaction mixture was stirred for about 5min at ambient temperature and then piperidine-1-carbonyl chloride(0.019 g, 0.13 mmol) was added. The reaction was heated at about 45° C.for about 18 h, cooled to ambient temperature, and concd under reducedpressure. The crude product was dissolved in DCM (5 mL) and washed withwater (3 mL), dried over anhydrous MgSO₄, filtered, and concd underreduced pressure. The material was purified by RP-HPLC (Table 1, Methodf) to give((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)(piperidin-1-yl)methanone(0.018 g, 8%): LC/MS (Table 1, Method b) R_(t)=1.80 min; MS m/z 367(M+H)⁺.

TABLE I.1 Examples prepared from1-((3R,4R)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine hydrochloride (Example #5, Step J) using General Procedure Iwith TEA R_(t) min m/z (Table 1, ESI+ Carbamoyl chloride Product Example# Method) (M + H)⁺ morpholine-4- carbonyl chloride

I.1.2* 1.48 (b) 369 4-methyl-1- piperazinecarbonyl chloridehydrochloride

I.1.3* 1.22 (b) 382

TABLE I.2 Examples prepared from1-(cis-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e] pyrazinehydrochloride (prepared using D from Preparation #Q.1 with NaOH, and Ewith 4 N HCl in 1,4-dioxane) using General Procedure I with TEA R_(t)min m/z (Table 1, ESI+ Carbamoyl chloride Product Example # Method) (M +H)⁺ 1- pyrrolidinecarbonyl chloride

I.2.1 1.63 (b) 353 dimethylcarbamoyl chloride

I.2.2 1.52 (b) 327

TABLE I.3 Example prepared from(R)-1-(piperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazinehydrochloride (Example #6, Step H) using General Procedure I with TEAR_(t) min m/z (Table 1, ESI+ Carbamoyl chloride Product Example #Method) (M + H)⁺ 1-pyrrolidinecarbonyl chloride

I.3.1* 1.53 (b) 339

General Procedure J: Formation of a Urea or a Thiourea Using CDI orThiocarbonyldiimidazole, Respectively

To a solution or slurry of an amine or amine salt (1-3 equiv, preferably1 equiv) in an organic solvent such as DCM, THF, or DMF (preferably DCM)at about −20-40° C. (preferably about 0° C.) is added an organic base,such as TEA, DIEA, pyridine (preferably TEA) (1-10 equiv, preferably 1-3equiv) followed by CDI or 1,1′-thiocarbonyldiimidazole (0.5-2 equiv,preferably 1 equiv). After about 0.5-24 h (preferably about 0.5-1 h), asecond amine or amine salt (1-10 equiv, preferably 3 equiv) is addedneat or as a solution or slurry in an organic solvent such as DCM, THF,or DMF (preferably DCM). The reaction is held at about 0° C. for about10-60 min (preferably about 15-30 min) and then the reaction is allowedto warm to ambient temperature. After about 1-48 h (preferably about12-16 h), the reaction mixture is partitioned between an organic solvent(such as EtOAc, DCM or 1,4-dioxane) and an aqueous base (such assaturated aqueous NaHCO₃ or saturated aqueous Na₂CO₃, preferablysaturated aqueous NaHCO₃). Optionally, the reaction mixture is concdunder reduced pressure and the residue is partitioned as above. Ineither case, the aqueous layer is then optionally extracted withadditional organic solvent such as EtOAc or DCM. The combined organiclayers may optionally be washed with brine and concd in vacuo or driedover anhydrous Na₂SO₄ or MgSO₄ and then decanted or filtered prior toconcentrating under reduced pressure to give the target compound.Intermediates and final compounds prepared via this General Procedurecan be optionally purified using one or more of the Purification Methodsdescribed above.

Preparation #J.1 tert-butyl1-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamothioyl)pyrrolidin-3-ylcarbamate

To a slurry of (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanaminehydrochloride (0.50 g, 1.5 mmol, Example #5, Step C) in DCM (10 mL) atabout 0° C. was added TEA (0.226 mL, 1.62 mmol). To the homogeneousreaction mixture was added a solution of 1,1′-thiocarbonyldiimidazole(0.29 g, 1.6 mmol) in DCM (10 mL). After about 30 min, a slurry oftert-butyl pyrrolidin-3-ylcarbamate (0.83 g, 4.4 mmol, TCI) in DCM (10mL) was added to the reaction mixture. After stirring for about 20 min,the reaction mixture was allowed to warm to ambient temperature. Afterstirring for about 15 h, saturated aqueous NaHCO₃ (30 mL) was added tothe reaction mixture. The organic layer was separated, concd in vacuo,and purified by chromatography on silica gel eluting with 20-40% EtOAcin DCM to provide tert-butyl1-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamothioyl)pyrrolidin-3-ylcarbamate(0.54 g, 69%) as a yellow glass: LC/MS (Table 1, Method a) R_(t)=2.37min; MS m/z: 531 (M+H)⁺.

General Procedure J.1: Formation of a Urea or a Thiourea Using CDI orThiocarbonyldiimidazole, Respectively

To a solution or slurry of an amine or amine salt (1-3 equiv, preferably1-2 equiv) in an organic solvent such as DCM, THF, or DMF (preferablyDMF) at about 20-80° C. (preferably about 65° C.) is optionally added anorganic base, such as TEA, DIEA, pyridine (preferably TEA) (1-10 equiv,preferably 1-5 equiv) followed by CDI or 1,1′-thiocarbonyldiimidazole(0.5-2 equiv, preferably 1 equiv). After about 0.5-24 h (preferablyabout 1-3 h), a second amine or amine salt (1-10 equiv, preferably 1-3equiv) is added neat or as a solution or slurry in an organic solventsuch as DCM, THF, or DMF (preferably DMF). The reaction is held at about20-80° C. (preferably about 65° C.) for about 2-24 h (preferably about 3h). If the reaction mixture is heated, it is cooled to ambienttemperature. The reaction mixture is partitioned between an organicsolvent (such as EtOAc, DCM or 1,4-dioxane) and an aqueous base (such assaturated aqueous NaHCO₃ or saturated aqueous Na₂CO₃, preferablysaturated aqueous NaHCO₃). Optionally, the reaction mixture is concdunder reduced pressure and the residue is partitioned as above. Ineither case, the aqueous layer is then optionally extracted withadditional organic solvent such as EtOAc or DCM. The combined organiclayers may optionally be washed with brine and concd in vacuo or driedover anhydrous Na₂SO₄ or MgSO₄ and then decanted or filtered prior toconcentrating under reduced pressure to give the target compound.Optionally, the reaction mixture is concd under reduced pressure and theresidue is directly purified.

Illustration of General Procedure J.1 Preparation #J.1.1(cis)-N-(2-cyclopropylethyl)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)pyrrolidine-1-carboxamide

To a solution of 2-cyclopropylethanamine (0.068 g, 0.804 mmol, Oakwood)in DMF (3 mL) was added CDI (0.150 g, 0.926 mmol). The solution wasstirred at about 65° C. for about 2 h.1-((cis)-4-ethylpyrrolidin-3-yl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine(0.250 g, 0.609 mmol, Example #36, step F) was added and the reactionmixture continued heating at about 65° C. After about 2 h, the reactionmixture was cooled to ambient temperature. The solvent was removed underreduced pressure. The crude material was purified by chromatography onsilica gel eluting with a gradient of 0-10% MeOH in DCM to give(cis)-N-(2-cyclopropylethyl)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)pyrrolidine-1-carboxamide(0.238 g, 64%) as product: LC/MS (Table 1, Method a) R_(t)=2.17 min; MSm/z: 522 (M+H)⁺.

TABLE J.1 Examples prepared from1-(cis)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e] pyrazinehydrochloride (prepared using D from Preparation #Q.1 with NaOH, and Ewith 4 N HCl in 1,4-dioxane) using General Procedure J with CDI R_(t)min m/z Amine or Amine (Table 1, ESI+ hydrochloride Product Example #Method) (M + H)⁺ azetidine-3- carbonitrile hydrochloride [AstaTech Inc]

J.1.1 1.48 (b) 364 2- aminoacetonitrile

J.1.2 1.37 (b) 338

TABLE J.2 Examples prepared from1-((3R,4R)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine hydrochloride (Example #5, Step J) using General Procedure Jwith CDI R_(t) min m/z Amine or Amine Example (Table 1, ESI+hydrochloride Product # Method) (M + H)⁺ pyrrolidine-3- carbonitrilehydrochloride [Tyger]

J.2.1*  1.51 (b) 378 (R)-pyrrolidine-2- carbonitrile hydrochloride[AstaTech Inc]

J.2.2*  1.61 (b) 378 (S)-pyrrolidine-2- carbonitrile hydrochloride[AstaTech Inc]

J.2.3*  1.63 (b) 378 (S)-2- (trifluoromethyl) pyrrolidine

J.2.4*  1.99 (b) 421 3,3-(difluoroazetidine hydrochloride

J.2.5*  1.71 (b) 375 azetidine

J.2.6*  1.51 (b) 339 (R)-3-fluoropyrrolidine hydrochloride

J.2.7*  1.59 (b) 371 3,3-difluoropyrrolidine hydrochloride

J.2.8*  1.71 (b) 389 (R)-pyrrolidin-2- ylmethanol

J.2.9*  1.45 (b) 383 3-methylpyrrolidine [Tyger]

J.2.10* 1.75 (b) 367 3-fluoroazetidine hydrochloride [ParkwayScientific]

J.2.11* 1.53 (b) 357 (S)-3-fluoropyrrolidine hydrochloride

J.2.12* 1.56 (b) 371 (R)-2- methylpyrrolidine

J.2.13* 1.74 (b) 367 hexamethyleneimine

J.2.14* 1.87 (b) 381 (R)-2- (trifluoromethyl) pyrrolidine

J.2.15* 2.03 (b) 421

TABLE J.3 Examples prepared from(R)-1-(piperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazinehydrochloride (Example #6, Step H) using General Procedure J with CDIand pyridine R_(t) min m/z Amine or Amine (Table 1, ESI+ hydrochlorideProduct Example # Method) (M + H)⁺ 3,3-difluoroazetidine hydrochloride

J.3.1*  1.56 (b) 361 3,3- difluoropyrrolidine hydrochloride

J.3.2*  1.60 (b) 375 piperidine-3- carbonitrile [ChemBridge-BB]

J.3.3*  1.55 (b) 378 azetidine-3- carbonitrile hydrochloride [AstaTechInc]

J.3.4*  1.36 (b) 350 (R)-2- (trifluoromethyl) pyrrolidine

J.3.5*  1.76 (b) 407 3,3- dimethylpyrrolidine hydrochloride [MatrixScientific]

J.3.6*  1.75 (b) 367 3,3- difluoropiperidine hydrochloride

J.3.7*  1.71 (b) 389 piperidine-4- carbonitrile [Oakwood]

J.3.8*  1.48 (b) 378 thiomorpholine 1,1-dioxide [TCI-Europe]

J.3.9*  1.31 (b) 403 4,4- dimethylpiperidine hydrochloride [MatrixScientific]

J.3.10* 1.93 (b) 381 4-chloropiperidine hydrochloride [AstaTech Inc]

J.3.11* 1.72 (b) 387

TABLE J.4 Examples prepared from1-((3R,4S)-4-isopropylpyrrolidin-3-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (prepared using Y from Example #D.1.143) usingGeneral Procedure J with CDI R_(t) min m/z Amine or Amine (Table 1, ESI+hydrochloride Product Example # Method) (M + H)⁺ Cyclobutanamine(Aldrich)

J.4.1 1.58 (a) 368General Procedure K: Formation of a Sulfonamide from an Amine

To a mixture of an amine or an amine salt (preferably 1 equiv) in anorganic solvent such as THF, DMA, DCM or DMF (preferably DMF) is addedan organic base such as TEA or DIEA (1-10 equiv, preferably 2-4 equiv)or an aqueous base such as saturated aqueous NaHCO₃ (5-20 equiv,preferably 5-10 equiv) (preferably an organic base) and a sulfonylchloride (0.9-3 equiv, preferably 1-1.5 equiv). The reaction mixture isstirred at about −10-25° C. (preferably at ambient temperature) forabout 0.5-150 h (preferably about 144 h). Optionally, additional base(1-10 equiv) and/or sulfonyl chloride (0.4-2 equiv) may be added at anypoint during the reaction time. The reaction is worked up using one ofthe following methods. Method 1: The reaction is diluted with water andextracted with an organic solvent such as DCM or EtOAc. The combinedorganic layers are optionally washed with brine, dried over anhydrousNa₂SO₄ or MgSO₄, filtered or decanted, and concd under reduced pressure.Method 2: The crude reaction mixture is purified by preparative HPLCdirectly or after the addition of organic solvent such as MeOH or DMF oran aqueous buffer such as 50 mM NH₄OAc with or without concentrating themixture under reduced pressure first. Method 3: The solvent is removedunder reduced pressure and the residue is partitioned between an organicsolvent such as DCM or EtOAc (preferably EtOAc) and water. The layersare separated and the organic layer is optionally washed with brine,dried over anhydrous Na₂SO₄ or MgSO₄, filtered or decanted, and concdunder reduced pressure. Method 4: The reaction is diluted with water andthe resulting solid is collected by vacuum filtration.

Illustration of General Procedure K Example #K.1N-((1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentyl)-3,3,3-trifluoropropane-1-sulfonamide

3,3,3-Trifluoropropane-1-sulfonyl chloride (0.194 g, 0.987 mmol, Matrix)was added dropwise to a solution of TEA (0.31 mL, 2.2 mmol) and3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentanamine(0.28 g, 1.1 mmol, Preparation #53) in DMF (10 mL). The resultingmixture was stirred at ambient temperature for about 144 h. The solventwas removed under reduced pressure and the residue was partitionedbetween EtOAc and water (20 mL each). The layers are separated and theorganic layer was washed with brine (30 mL), dried over anhydrous MgSO₄,filtered, and concd under reduced pressure. The residue was purified byusing General Procedure AA (Table 2, Method 9, R_(t)=17.7 min, or=negative) to giveN-((1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentyl)-3,3,3-trifluoropropane-1-sulfonamide(0.021 g, 4.6%) as a white solid: LC/MS (Table 1, Method a) R_(t)=1.79min; MS m/z 416 (M+H)⁺.

TABLE K.1 Examples prepared from(1S,3R,4S)-3-methyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine (Preparation #19.1) using GeneralProcedure K R_(t) min m/z (Table 1, ESI+ Sulfonyl chloride ProductExample # Method) (M + H)⁺ 5- methylisoxazole- 4-sulfonyl chloride[Maybridge]

K.1.1* 1.91 (a) 402

TABLE K.2 Example prepared from1-(cis)-4-methylpiperidin-3-yl)-6H-imidazo[1,5- a]pyrrolo[2,3-e]pyrazinehydrochloride (prepared using D from Preparation #Q.1 with NaOH, and Ewith 4N HCl in 1,4-dioxane) using General Procedure K R_(t) min (Table1, m/z ESI+ Sulfonyl chloride Product Example # Method) (M + H)⁺cyclopropanesulfonyl chloride

K.2.1 1.66 (b) 360

TABLE K.3 Examples prepared from4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)bicyclo[2.2.2]octan-1-amine hydrobromide (Preparation #F.1) usingGeneral Procedure K R_(t) min (Table 1, m/z ESI+ Sulfonyl chlorideProduct Example # Method) (M + H)⁺ Cyclopropanesulfonyl chloride

K.3.1 1.59 (a) 386

TABLE K.4 Examples prepared from(3S,5R)-5-ethyl-1-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)pyrrolidin-3-amine (Preparation #TTT.1) using GeneralProcedure K R_(t) min (Table 1, m/z ESI+ Sulfonyl chloride ProductExample # Method) (M + H)⁺ 3,3,3-trifluoropropane-1- sulfonyl chloride(Matrix)

K.4.1* 1.86 (a) 431

TABLE K.5 Examples prepared from (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine (Prepared fromExample #8 Step M using D) using General Procedure K R_(t) min (Table 1,m/z ESI+ Sulfonyl chloride Product Example # Method) (M + H)⁺2,2,2-trifluoroethane-1- sulfonyl chloride

K.5.1 1.89 (a) 417General Procedure K.1: Formation of a Sulfonamide from an Amine orNitrogen Containing Heterocycle (Additional Conditions)

To a mixture of an amine, an amine salt or a nitrogen containingheterocycle (preferably 1 equiv) in an organic solvent such as THF, DMA,DCM or DMF (preferably DMF) is added an organic base such as TEA or DIEA(1-10 equiv, preferably 2-4 equiv) or an aqueous base such as saturatedaqueous NaHCO₃ (5-20 equiv, preferably 5-10 equiv) or an inorganic basesuch as NaH (1-10 equiv, preferably 1-3 equiv) and a sulfonyl chloride(0.9-3 equiv, preferably 1-1.5 equiv). The reaction mixture is stirredat about −10-25° C. (preferably at about 0° C.) for about 5 min-150 h(preferably about 90 min). Optionally, additional base (1-10 equiv)and/or sulfonyl chloride (0.4-2 equiv) may be added at any point duringthe reaction time. In cases where a halogen is present, the halogen mayeliminate and the alkene may be obtained. The reaction is worked upusing one of the following methods. Method 1: The reaction is dilutedwith water and extracted with an organic solvent such as DCM or EtOAc.The combined organic layers are optionally washed with saturated aqueousbase and brine, dried over anhydrous Na₂SO₄ or MgSO₄, filtered ordecanted, and concd under reduced pressure. Method 2: The crude reactionmixture is purified by preparative HPLC directly or after the additionof organic solvent such as MeOH or DMF or an aqueous buffer such as 50mM NH₄OAc with or without concentrating the mixture under reducedpressure first. Method 3: The solvent is removed under reduced pressureand the residue is partitioned between an organic solvent such as DCM orEtOAc (preferably EtOAc) and water. The layers are separated and theorganic layer is optionally washed with brine, dried over anhydrousNa₂SO₄ or MgSO₄, filtered or decanted, and concd under reduced pressure.Method 4: The reaction is diluted with water and the resulting solid iscollected by vacuum filtration.

Illustration of General Procedure K.1 Preparation #K.1N-((1S,3R,4S)-3-ethyl-4-(5-nitro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)cyclopentyl)cyclopropanesulfonamide

To a solution ofN-((1S,3R,4S)-3-ethyl-4-(5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)cyclopentyl)cyclopropanesulfonamide(Example #23, Step G) (0.123 g, 0.314 mmol) in DMF (3.0 mL) at about 0°C. was added NaH (60% in mineral oil, 0.015 g, 0.37 mmol). The reactionmixture was stirred for about 5 min. 4-Methylbenzene-1-sulfonyl chloride(0.060 g, 0.314 mmol) was added and the reaction mixture was stirred forabout 30 min. NaH (60% in mineral oil, 0.007 g, 0.18 mmol) was added andthe reaction mixture was stirred for about 10 min. NaH (60% in mineraloil, 0.005 g, 0.12 mmol) was added and the reaction mixture was stirredfor about 15 min. 4-Methylbenzene-1-sulfonyl chloride (0.012 g, 0.063mmol) was added and the reaction mixture was stirred for about 40 min.The reaction mixture was concd under reduced pressure. The residue wasdissolved in EtOAc (25 mL) and washed with water (15 mL). The organiclayer was separated, dried over anhydrous MgSO₄, filtered and concdunder reduced pressure to giveN-((1S,3R,4S)-3-ethyl-4-(5-nitro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)cyclopentyl)-cyclopropanesulfonamide(0.218 g) as a red-orange oil containing 40 mol % DMF and 1 equiv EtOAc:LC/MS (Table 1, Method n) R_(t)=0.88 min; MS m/z 548 (M+H)⁺.

General Procedure L: Displacement of an Aryl or Heteroaryl Halide withan Amine

To a microwave vessel or a round bottom flask is added an amine or anamine salt (preferably 1 equiv), an aryl or heteroaryl halide (1-10equiv, preferably 1.5 equiv), a solvent (such as MeCN, n-PrOH, n-BuOH,toluene, DMSO, DMF, or EtOH, preferably n-PrOH[microwave] or DMF[thermal heating]), and a base (such as K₂CO₃, Na₂CO₃, TEA or DIEA,preferably TEA, DIEA, or K₂CO₃, 1-5 equiv, preferably 2-4 equiv). Thereaction mixture is heated at about 40-220° C. thermally (preferablyabout 65° C.) for about 0.5-16 h (preferably about 8.5 h) or issubjected to microwave heating at about 100-200° C. (preferably about130-150° C.) for about 0.5-8 h (preferably about 0.5-2 h). In caseswhere the reaction does not proceed to completion as monitored by TLC,LC/MS, or HPLC, the reaction may be resubjected to thermal heating atabout 40-220° C. (preferably about 65° C.) for about 0.5-8 h (preferablyabout 1-2 h) or microwave heating at about 120-200° C. (preferably about130-150° C.) for an additional about 1-8 h (preferably about 0.5-2 h)with the optional addition of more aryl or heteroaryl halide (1-10equiv, preferably 1.5 equiv) and/or base (such as K₂CO₃, Na₂CO₃, TEA orDIEA, preferably TEA, DIEA or K₂CO₃, 1-5 equiv, preferably 2-4 equiv).This process is repeated until the reaction proceeds no further. Aftercooling to ambient temperature, the reaction is worked up using one ofthe following methods. Method 1: The reaction is concd under reducedpressure. Method 2: A reaction mixture containing a precipitate may befiltered to collect the target compound, while optionally washing withorganic solvent or solvents such as Et₂O, DCM and/or petroleum ether.Method 3: The reaction mixture is diluted with an organic solvent suchas MeOH, silica gel is added, and the mixture is concd under reducedpressure to prepare for separation by chromatography with solid loading.Method 4: The reaction mixture is concd under reduced pressure prior tothe addition of an organic solvent such as EtOAc or DCM and is thenoptionally washed with water and/or brine, dried over anhydrous Na₂SO₄or MgSO₄, filtered or decanted, and concd under reduced pressure. Method5: An organic solvent such as EtOAc or DCM is added with the optionaladdition of water or brine and the layers are separated. The aqueouslayer is then optionally extracted with additional organic solvent suchas EtOAc or DCM. The combined organic layers are optionally washed withbrine or water, dried over anhydrous MgSO₄ or Na₂SO₄, filtered ordecanted, and concd under reduced pressure.

Illustration of General Procedure L Preparation #L.1(S)-5-(3-((6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)methyl)pyrrolidin-1-yl)pyrazine-2-carbonitrile

A mixture of(S)-1-(pyrrolidin-3-ylmethyl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine(0.160 g, 0.404 mmol, prepared using B from Preparation #A.1 and E withHCl), 2-chloro-5-cyanopyrazine (0.084 g, 0.60 mmol, ArkPharm) and DIEA(0.28 mL, 1.6 mmol) in n-PrOH (2.0 mL) was heated in a CEM microwave atabout 150° C. for about 30 min (250 psi maximum pressure, 10 min maximumramp, 200 maximum watts). The reaction mixture was cooled to ambienttemperature and DCM (20 mL) was added. The solution was washed withwater (20 mL) and brine (20 mL). The organic layer was separated, driedover anhydrous MgSO₄, filtered, and concd under reduced pressure. Theresidue was taken up in DCM (10 mL), adsorbed onto silica gel (1 g), andpurified by silica gel chromatography eluting with 100% EtOAc to give apink solid. The material was triturated with a mixture of EtOAc (10 mL)and 10% MeOH in DCM (10 mL). The insoluble material was collected byfiltration to give(S)-5-(3-((6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)methyl)pyrrolidin-1-yl)pyrazine-2-carbonitrileas an off-white solid (0.056 g, 27%): LC/MS (Table 1, Method c)R_(t)=1.34 min; MS m/z: 500 (M+H)⁺.

TABLE L.1 Examples prepared from1-(cis)-4-methylpiperidin-3-yl)-6H-imidazo[1,5- a]pyrrolo[2,3-e]pyrazinehydrochloride (prepared using D from Preparation #Q.1 with NaOH, and Ewith 4N HCl in 1,4-dioxane) using General Procedure L m/z Ex- R_(t) minESI+ ample (Table 1, (M + Heteroaryl Halide Product # Method) H)⁺6-chloropyridazine- 3-carbonitrile [ArkPharm]

L.1.1 1.68 (b) 359 2-chloro-5- cyanopyrazine [ArkPharm]

L.1.2 1.81 (b) 359 6- chloronicotinonitrile

L.1.3 1.88 (b) 358 2-chlorothiazole-5- carbonitrile [ArkPharm]

L.1.4 1.84 (b) 364

TABLE L.2 Example prepared from1-((3R,4R)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine hydrochloride (Example #5, Step J) usingGeneral Procedure L R_(t) min (Table 1, m/z ESI+ Heteroaryl HalideProduct Example # Method) (M + H)⁺ 2-chlorobenzoxazole [TCI America]

L.2.1* 1.94 (b) 373

TABLE L.3 Examples prepared from(R)-8-(piperidin-3-yl)-3H-imidazo[1,2-a]pyrrolo[2,3- e]pyrazinehydrobromide and (S)-8-(piperidin-3-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine hydrobromide (Example #3, Step G) using General Procedure LR_(t) min (Table 1, m/z ESI+ Aryl chloride Product Example # Method)(M + H)⁺ 2-chloro-5-cyanopyrazine [ArkPharm]

L.3.1 1.71 (a) 345

General Procedure M: Boc-Protection of an Amine

To a solution of an amine or amine salt (preferably 1 equiv) in anorganic solvent (for example MeCN, 1,4-dioxane or THF, preferably THF)is added an aqueous base such as Na₂CO₃, NaOH, K₂CO₃ or NaHCO₃ (2-20equiv, preferably 2-10 equiv of Na₂CO₃) or an organic base such as TEAor DIEA (1-5 equiv, preferably 1-2 equiv of TEA) followed by addition ofdi-tert-butyl dicarbonate (1-3.0 equiv, preferably 1.2 equiv). Theaddition of base is optional if an amine salt is not used. The reactionis stirred at about 10-40° C. (preferably ambient temperature) for about2-24 h (preferably about 2-6 h) and worked up using one of the followingmethods. Method 1: An organic solvent (such as Et₂O, EtOAc or DCM) andwater are added and the layers are separated. The aqueous layer isextracted with additional organic solvent and the combined organiclayers may be optionally washed with brine, dried over anhydrous Na₂SO₄or MgSO₄, and then decanted or filtered prior to concentrating underreduced pressure. Method 2: The reaction mixture is partitioned betweenan organic solvent (such as Et₂O, EtOAc or DCM) and aqueous acid (suchas HCl). The acidic layer is extracted with additional organic solventand the combined organic layers may be optionally washed with brine. Theorganic layer is optionally dried over anhydrous Na₂SO₄ or MgSO₄, andthen decanted or filtered prior to concentrating under reduced pressure.

Illustration of General Procedure M Preparation #M.1*(1R,3S)-3-((tert-butoxycarbonylamino)methyl)cyclopentanecarboxylic acid

To a solution of (1R,3S)-3-(aminomethyl)cyclopentanecarboxylic acid(0.500 g, 3.49 mmol, AFID) in THF (4 mL) and water (4 mL) was addedNa₂CO₃ (1.11 g, 10.5 mmol) and di-tert-butyl dicarbonate (0.915 g, 4.19mmol). The reaction was stirred at ambient temperature for about 4 h.EtOAc (15 mL) and aqueous HCl (1 N, 15 mL) were added and the layerswere separated. The aqueous layer was extracted with EtOAc (2×10 mL) andthe combined organic layers were washed with brine (10 mL). The organiclayer was dried over anhydrous Na₂SO₄, filtered, and concd under reducedpressure to give(1R,3S)-3-((tert-butoxycarbonylamino)methyl)cyclopentanecarboxylic acid(0.300 g, 35%). ¹H NMR (DMSO-d₆) δ 11.97 (s, 1H), 6.83 (s, 1H),2.89-2.86 (t, J=8.0 Hz, 2H), 2.73-2.58 (m, 1H), 2.04-1.87 (m, 2H),1.82-1.68 (m, 2H), 1.68-1.58 (m, 1H), 1.37 (s, 9H), 1.34-1.19 (m, 2H).

General Procedure M.1: Boc-Protection of a Nitrogen-Containing Compound

To a nitrogen-containing compound (preferably 1 equiv) in an organicsolvent (for example DCM, MeCN, 1,4-dioxane or THF, preferably DCM) isadded an aqueous base such as Na₂CO₃, NaOH, K₂CO₃ or NaHCO₃ (preferablyNa₂CO₃, 2-20 equiv, preferably 2-10 equiv) or an organic base such asTEA or DIEA (preferably TEA, 1-5 equiv, preferably 1-2 equiv) followedby addition of di-tert-butyl dicarbonate (1-3 equiv, preferably 1.2equiv). DMAP (0.1-2 equiv, preferably 0.1 equiv) is optionally added tothe reaction mixture. The reaction is stirred at about 10-40° C.(preferably rt) for about 0.5-24 h (preferably about 1 h) and worked upusing one of the following methods. Method 1: An organic solvent (suchas Et₂O, EtOAc or DCM) and water are added and the layers are separated.The aqueous layer is optionally extracted with additional organicsolvent and the combined organic layers may be optionally washed withbrine, dried over anhydrous Na₂SO₄ or MgSO₄, and then decanted orfiltered prior to concentrating under reduced pressure. Method 2: Thereaction mixture is partitioned between an organic solvent (such asEt₂O, EtOAc or DCM) and aqueous acid (such as HCl). The acidic layer isextracted with additional organic solvent and the combined organiclayers may be optionally washed with brine. The organic layer isoptionally dried over anhydrous Na₂SO₄ or MgSO₄, and then decanted orfiltered prior to concentrating under reduced pressure. Method 3: Wateror an aqueous solution (such as brine) is added and the layers areseparated. The aqueous layer is optionally extracted with additionalorganic solvent (such as Et₂O, EtOAc or DCM) and the combined organiclayers may be optionally washed with brine, dried over anhydrous Na₂SO₄or MgSO₄, and then decanted or filtered prior to concentrating underreduced pressure.

Illustration of General Procedure M.1 Preparation #M.1.1 t-butylcyclopropylsulfonyl(cis-3-methyl-4-propionylcyclopentyl)carbamate

To a solution ofN-(cis-3-methyl-4-propionylcyclopentyl)cyclopropanesulfonamide (2.70 g,10.4 mmol, prepared using H fromcis-4-(cyclopropanesulfonamido)-2-methylcyclopentanecarboxylic acid(WO2009152133) with N,O-dimethylhydroxylamine hydrochloric acid, MMMMwith ethylmagnesium chloride) in DCM (52 mL) was added TEA (1.60 mL,11.5 mmol), di-tert-butyl dicarbonate (2.90 mL, 12.5 mmol), and DMAP(0.127 g, 1.04 mmol). The reaction was stirred at rt for about 1 h.Water (50 mL) was added and the layers were separated. The aqueous layerwas extracted with DCM (3×30 mL) and the combined organic layer wasconcd under reduced pressure. The product was purified by silica gelchromatography eluting with a gradient of 0-50% EtOAc in heptane to givet-butylcyclopropylsulfonyl(cis-3-methyl-4-propionylcyclopentyl)carbamate (3.71g, 99%) as a white solid: LC/MS (Table 1, Method b) R_(t)=2.62 min; MSm/z: 360 (M+H)⁺.

General Procedure N: Cbz-Protection of an Amine

A solution of an amine or an amine salt (preferably 1 equiv) and a base(for example, Na₂CO₃ or NaOH, 1-3 equiv, preferably Na₂CO₃, 1.6 equiv)in water or aqueous organic solvent (for example, water/1,4-dioxane orwater/MeCN, preferably water/1,4-dioxane) is stirred at ambienttemperature for about 1-10 min (preferably 5 min). A solution of benzyl2,5-dioxopyrrolidin-1-yl carbonate (1-2 equiv, preferably 1.0 equiv) inan organic solvent such as 1,4-dioxane or MeCN is added to the reaction.The reaction is stirred at ambient temperature for about 8-144 h(preferably about 72 h). Optionally, the reaction mixture is concd underreduced pressure. The resulting aqueous solution is diluted with anorganic solvent (such as EtOAc or DCM). The organic extracts areoptionally washed with water and/or brine, dried over anhydrous Na₂SO₄or MgSO₄, filtered or decanted, and concd under reduced pressure.Alternatively, the resulting aqueous solution is acidified by adding anacid such as aqueous NH₄Cl or HCl and is then extracted with an organicsolvent (such as EtOAc or DCM).

Illustration of General Procedure N Preparation #N.1 methyl4-(benzyloxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylate

To a solution of methyl 4-aminobicyclo[2.2.2]octane-1-carboxylatehydrochloride (1.16 g, 5.29 mmol, Prime Organics) in 1,4-dioxane (15 mL)was added a solution of Na₂CO₃ (0.90 g, 8.49 mmol) in water (15 mL). Thereaction mixture was stirred for about 5 min at ambient temperature.Benzyl 2,5-dioxopyrrolidin-1-yl carbonate (1.32 g, 5.29 mmol) was addedand the reaction mixture was stirred at ambient temperature for about 72h. The reaction mixture was diluted with EtOAc (50 mL). The layers wereseparated and the aqueous layer was extracted with EtOAc (2×20 mL). Thecombined organic layers were dried over anhydrous MgSO₄, filtered, andconcd under reduced pressure to give methyl4-(benzyloxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylate (1.68 g,95%): LC/MS (Table 1, Method a) R_(t)=2.44 min; MS m/z: 318 (M+H)⁺.

General Procedure O: Reduction of a Pyridine

A substituted pyridine (preferably 1 equiv) is dissolved in an organicsolvent (such as AcOH, EtOH, or MeOH; preferably AcOH if using a ParrShaker or EtOH if using an H-cube™). A suitable catalyst such asplatinum (IV) oxide or Pd/C (0.05-0.20 equiv, preferably 0.05-0.10 equivplatinum (IV) oxide for a Parr Shaker reaction or ThalesNano CatCart® 10wt % Pd/C catalyst cartridges for an H-Cube™) is used for the reductionunder an atmosphere of hydrogen at about 15-1450 psi (preferably about220 psi for a Parr Shaker or preferably 1305 psi for an H-Cube™) Thereaction is run for about 1-10 d (preferably about 3-5 d) at about20-100° C. (preferably about 25° C.) for the Parr Shaker or at about 1-3mL/min (preferably 1 mL/min) at about 25-100° C. (preferably about 80°C.) for about 1-10 h (preferably about 3 h) for an H-Cube™. The reactionmixture is filtered through Celite® if run in a Parr shaker and concdunder reduced pressure in either case.

Illustration of General Procedure O Preparation #O.1cis-4-(trifluoromethyl)piperidine-3-carboxylic acid

A solution of 4-(trifluoromethyl)nicotinic acid (1.50 g, 7.85 mmol) inEtOH (78 mL) was passed through an H-Cube™ equipped with a ThalesNanoCatCart® 10 wt % Pd/C catalyst cartridge at about 1.0 mL/min, at about80° C., under about 1305 psi of hydrogen. After about 3 h, the solventwas removed under reduced pressure to affordcis-4-(trifluoromethyl)piperidine-3-carboxylic acid (1.55 g, 100%crude): LC/MS (Table 1, Method b) R_(t)=0.54 min; MS m/z: 198 (M+H)⁺.

General Procedure P: Reduction of a Carbonyl to an Alcohol

A reducing agent (1.0-3.0 equiv, preferably 1.25 equiv), such as LAH,DIBAL-H, NaBH₄ or LiBH₄ (preferably DIBAL-H), is added eitherportionwise as a solid or dropwise as a solution in an organic solvent(such as THF, Et₂O, EtOH or MeOH, preferably THF) to a solution of acarbonyl compound (preferably 1 equiv) in an organic solvent (such asTHF, Et₂O, EtOH or MeOH, preferably MeOH) at about −40-50° C.(preferably ambient temperature). The reaction mixture is stirred forabout 1-20 h (preferably about 16 h) before quenching with an aqueoussolution (such as NH₄Cl or NaHCO₃, preferably saturated aqueous NH₄Cl).The reaction is stirred for about 10 min-3 h (preferably about 20-30min) and then the solution is partitioned with an organic solvent (suchas EtOAc, Et₂O or DCM, preferably Et₂O). The organic layer is washedwith brine, dried over anhydrous Na₂SO₄ or MgSO₄, filtered, and concdunder reduced pressure.

Illustration of General Procedure P Preparation #P.1 ethyl2-ethyl-4-hydroxycyclopentanecarboxylate

To ethyl 2-ethyl-4-oxocyclopentanecarboxylate (10 g, 54.3 mmol, Example#8, Step G) in MeOH (143 mL) was added NaBH₄ (2.57 g, 67.8 mmol)portionwise. The resulting suspension was stirred for about 16 h atambient temperature then saturated aqueous NH₄Cl (240 mL) was added. Thereaction mixture was stirred for about 20 min then the solution waspartitioned with Et₂O (300 mL). The organic layer was separated and theaqueous layer was washed with Et₂O (2×150 mL). The combined organiclayers were washed with brine (100 mL), dried over anhydrous MgSO₄,filtered, and concd under reduced pressure. The product was purified bysilica gel chromatography (220 g) eluting with a gradient of 30-70%EtOAc in heptane to give ethyl 2-ethyl-4-hydroxycyclopentanecarboxylate(8.51 g, 84%, predominantly (1S,2R,4S)-ethyl2-ethyl-4-hydroxycyclopentanecarboxylate and (1R,2S,4R)-ethyl2-ethyl-4-hydroxycyclopentanecarboxylate) as a clear oil: LC/MS (Table1, Method b) R_(t)=2.02 min; MS m/z: 187 (M+H)⁺.

TABLE P.1 Examples prepared using General Procedure P with DIBAL-H R_(t)min (Table 1, m/z ESI+ Carbonyl compound Product Example # Method) (M +H)⁺ ethyl 2-((1S,3R,4S)-3-ethyl-4- (6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin- 1-yl)cyclopentyl)acetate (Preparation#W.1.2)

P.1.1 1.47 (b) 300 ethyl 2-((1R,3R,4S)-3-ethyl-4- (6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin- 1-yl)cyclopentyl)acetate (Preparation#W.1.1)

P.1.2 1.47 (b) 300

General Procedure Q: Cyclization of an Amide Using a DithiadiphosphetaneReagent

To a solution of an amide (preferably 1 equiv) in an organic solvent(preferably 1,4-dioxane) is added a dithiadiphosphetane reagent such asLawesson's reagent or Belleau's reagent(2,4-bis(4-phenoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide)(preferably Lawesson's reagent) (0.5-2.0 equiv, preferably 0.6 equiv).The reaction is heated at about 25-120° C. (preferably about 80° C.) forabout 0.5-10 h (preferably about 1 h). The reaction mixture is cooled toambient temperature and is optionally concd under reduced pressure togive a residue. The reaction mixture or residue is partitioned betweenan organic solvent (such as DCM or EtOAc, preferably EtOAc) and water,an aqueous base (such as saturated aqueous NaHCO₃) or brine. The layersare separated and the organic layer is optionally washed with water, anaqueous base (such as saturated aqueous NaHCO₃) and/or brine, dried overanhydrous Na₂SO₄ or MgSO₄, filtered, and concd under reduced pressure togive a thioamide. To a solution of thioamide (preferably 1 equiv) in anorganic solvent (preferably 1,4-dioxane) is added a Lewis acid, such asdiacetoxymercury, mercury dichloride, mercury (II) trifluoroacetate,silver trifluoroacetate, silver nitrate, copper bromide (preferablydiacetoxymercury or mercury (II) trifluoroacetate) (1-3 equiv,preferably 1 equiv). The reaction mixture is stirred at about 20-60° C.(preferably ambient temperature) for about 0.5-4 h (preferably about 1h). Optionally, additional Lewis acid (preferably diacetoxymercury ormercury (II) trifluoroacetate) (0.2-1.0 equiv, preferably 0.6 equiv) isadded and the reaction is continued for about 10 min-3 h (preferablyabout 15 min). The reaction mixture is optionally diluted with saturatedsodium thiosulfate, water, and/or an organic solvent (preferably EtOAc)and is filtered, preferably through a pad of Celite®. The pad of Celite®can be rinsed with additional organic solvent (preferably EtOAc or DCM).The filtrate is concd under reduced pressure. The crude material isoptionally partitioned between an organic solvent (such as EtOAc or DCM)and washed with saturated sodium thiosulfate and/or water, an aqueousbase (such as saturated aqueous NaHCO₃) and/or brine, dried overanhydrous Na₂SO₄ or MgSO₄, filtered, and concd under reduced pressure.

Illustration of General Procedure Q Preparation #Q.1 cis-tert-butyl4-methyl-3-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate

A round bottom flask was charged with cis-tert-butyl4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)piperidine-1-carboxylate(5.62 g, 10.6 mmol, prepared using 0 from 4-methylnicotonic acid, M, Hfrom Example #5, Step C, HATU and DIEA) and Lawesson's reagent (3.0 g,7.4 mmol) in 1,4-dioxane (100 mL). The reaction was heated at about 80°C. for about 1 h, cooled to ambient temperature, and concd under reducedpressure. The crude product was dissolved in EtOAc (200 mL) and washedwith saturated aqueous NaHCO₃ (3×100 mL). The organic layer wasseparated, dried over anhydrous MgSO₄, filtered, and concd under reducedpressure. The material was purified by silica gel chromatography elutingwith a gradient of 0-5% MeOH in DCM to afford cis-tert-butyl4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamothioyl)piperidine-1-carboxylate(5.2 g, 90%): LC/MS (Table 1, Method b) R_(t)=2.65 min; MS m/z: 544(M+H)⁺. A round bottom flask was charged with cis-tert-butyl4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamothioyl)piperidine-1-carboxylate(2.6 g, 4.8 mmol) and mercury (II) trifluoroacetate (2.1 g, 4.8 mmol) in1,4-dioxane (72 mL) and stirred at ambient temperature for about 1 h.The reaction mixture was filtered through a pad of Celite®. The Celite®pad was rinsed with DCM (30 mL) and EtOAc (30 mL). The filtrate wasconcd under reduced pressure. The residue was dissolved in DCM (50 mL)and washed with saturated aqueous sodium thiosulfate (10 mL), andsaturated aqueous NaHCO₃ (25 mL), dried over anhydrous MgSO₄, filtered,and concd under reduced pressure. The material was purified by silicagel chromatography eluting with a gradient of 0-5% MeOH in DCM to affordcis-tert-butyl-4-methyl-3-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate(2.2 g, 90%): LC/MS (Table 1, Method b) R_(t)=2.57 min; MS m/z: 510(M+H)⁺.

General Procedure R: Formation of a Bromomethyl Ketone from an Acid

To a solution of a carboxylic acid (preferably 1 equiv) in an organicsolvent (DCM or DCE, preferably DCM) is slowly added oxalyl chloride(1.2-3.0 equiv, preferably 2.2 equiv) followed by dropwise addition ofDMF (0.01-0.20 equiv, preferably about 0.15 equiv). The reaction isstirred at about 0-40° C. (preferably ambient temperature) for about3-24 h (preferably about 14 h) before it is concd under reduced pressureto a constant weight to give the crude acid chloride. A solution of acrude acid chloride (preferably 1 equiv) in an organic solvent (such asTHF, MeCN, Et₂O, or THF/MeCN, preferably THF/MeCN) is added totrimethylsilyldiazomethane (2.0 M in Et₂O) or diazomethane solution inEt₂O (prepared from Diazald® according to Aldrich protocol or J.Chromatogr. Sci. 1991, 29, 8) (2-10 equiv, preferably 3.5 equiv oftrimethylsilyldiazomethane) at about 20-20° C. (preferably about 0° C.)in a suitable organic solvent such as THF, MeCN, Et₂O, or THF/MeCN(preferably THF/MeCN). The reaction mixture is stirred for about 0.5-5 h(preferably about 3 h) at about 20-20° C. (preferably about 0° C.)before the dropwise addition of 48% aqueous HBr (5-40 equiv, preferablyabout 10 equiv). After about 0-30 min, (preferably about 5 min) thereaction mixture can be concd to dryness to give the desired product,neutralized by a dropwise addition of saturated aqueous NaHCO₃ or isoptionally washed with brine after optional addition of an organicsolvent (such as EtOAc or DCM, preferably EtOAc). In cases where thereaction mixture is subjected to an aqueous work-up, the organic layeris dried over anhydrous Na₂SO₄ or MgSO₄ (preferably MgSO₄), filtered,and concd under reduced pressure.

Illustration of General Procedure R Preparation #R.12-bromo-1-(4-(dibenzylamino)-2-methylcyclopentyl)ethanone

To a solution of 4-(dibenzylamino)-2-methylcyclopentanecarboxylic acid(7.34 g, 22.7 mmol, Preparation #TT.1) in DCM (100 mL), oxalyl chloride(4.37 mL, 49.9 mmol) was slowly added followed by a dropwise addition ofDMF (0.26 mL, 3.4 mmol). The mixture was stirred at ambient temperaturefor about 14 h and the solvent was removed under reduced pressure toyield 4-(dibenzylamino)-2-methylcyclopentanecarbonyl chloride as a beigesolid. The solid was dissolved in THF and MeCN (1:1, 100 mL) and addedto a solution of trimethylsilyldiazomethane (2 M in Et₂O, 39.7 mL, 79.4mmol) in 1:1 mixture of THF and MeCN (100 mL) at about 0° C. Theresulting mixture was stirred at about 0° C. for about 3 h and then wasquenched by dropwise addition of 48% aqueous HBr (25 mL, 221 mmol). Theresulting mixture was neutralized by dropwise addition of saturatedaqueous NaHCO₃ (300 mL) and the layers were separated. The organic layerwas dried over anhydrous MgSO₄, filtered, and concd under reducedpressure. The residue was purified by silica gel flash chromatographyeluting with a gradient of 5-45% EtOAc in heptane to yield2-bromo-1-(4-(dibenzylamino)-2-methylcyclopentyl)ethanone (6.3 g, 69%)as a yellow oil: LC/MS (Table 1, Method a) R_(t)=2.90 min; MS m/z 400,402 (1:1) (M+H)⁺.

General Procedure S: N-Alkylation Using Alkyl Halide or α-Haloketone

A round bottom flask is charged with a base such as NaH (60% dispersionin mineral oil), K₂CO₃, or Cs₂CO₃ (preferably NaH (60% dispersion inmineral oil), 0.9-1.5 equiv, preferably 0.95 equiv) and an organicsolvent (such as DMF or NMP, preferably DMF). The mixture is cooled toabout −10° C. to 10° C. (preferably about 0° C.) and a solution of anappropriately substituted amine (preferably 1 equiv) in an organicsolvent (such as DMF) is added. The reaction mixture is stirred forabout 5-90 min (preferably about 15-30 min) at about −10° C. to ambienttemperature (preferably about 0° C.) followed by the addition of analkyl halide or α-haloketone (1-2 equiv, preferably 1.2 equiv).Alternatively, a solution of an amine and a base in an organic solventmay be added to a solution of an alkyl halide or α-haloketone in anorganic solvent at about 0° C. The reaction mixture is stirred at about−10° C. to ambient temperature (preferably ambient temperature) forabout 0.5-2 h (preferably about 1 h). The organic solvent is removedunder reduced pressure. Optionally, the crude mixture may be dilutedwith water and an organic solvent (for example, EtOAc or DCM). Thelayers are separated and the aqueous layer is extracted further withorganic solvent (such as EtOAc and/or DCM). The combined organic layersare optionally washed with brine, dried over anhydrous MgSO₄, filtered,and concd to dryness under reduced pressure.

Illustration of General Procedure S Preparation #S.1 tert-butyl2-(4-(dibenzylamino)-2-methylcyclopentyl)-2-oxoethyl(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)carbamate

To a suspension of NaH (60% dispersion in mineral oil, 0.058 g, 1.45mmol) in DMF (5 mL) was added a solution of tert-butyl5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (0.59 g, 1.519 mmol,Example #3, Step E) in DMF (5 mL) dropwise at about 0° C. The resultingmixture was stirred at this temperature for about 30 min and then addeddropwise to a solution of2-bromo-1-(4-(dibenzylamino)-2-methylcyclopentyl)ethanone (0.73 g, 1.823mmol, Preparation #R.1) in DMF (10 mL). The resulting mixture wasstirred at about 0° C. for about 1 h and the solvent was removed underreduced pressure. The residue was partitioned between saturated aqueousNaHCO₃ and EtOAc (100 mL each). The organic phase was dried overanhydrous MgSO₄ and concd under reduced pressure to yield tert-butyl2-(4-(dibenzylamino)-2-methylcyclopentyl)-2-oxoethyl(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)carbamate(1.04 g, 97%) as a yellow amorphous solid: LC/MS (Table 1, Method a)R_(t)=3.30 min; MS m/z 708 (M+H)⁺.

General Procedure S.1: N-Alkylation Using Alkyl Halide, α-Haloketone orα-Haloamide

A round bottom flask is charged with a base such as NaH (60% dispersionin mineral oil), K₂CO₃, or Cs₂CO₃ (preferably NaH (60% dispersion inmineral oil), 0.9-1.5 equiv, preferably 0.95 equiv) and an organicsolvent (such as DMF, DCM, 1,4-dioxane, or NMP, preferably DMF). Themixture is cooled to about −10° C. to ambient temperature (preferablyabout 0° C.) and a solution of an appropriately substituted amine(preferably 1 equiv) in an organic solvent (such as DMF) is added.Alternatively, the base may be added portionwise to a solution of theamine and an organic solvent at about 0° C. to ambient temperature. Thereaction mixture is stirred for about 5-90 min (preferably about 15-30min) at about −10° C. to ambient temperature (preferably about 0° C.)followed by the addition of an alkyl halide, α-haloketone, orα-haloamide (1-2 equiv, preferably 1.2 equiv). Alternatively, a solutionof an amine and a base in an organic solvent may be added to a solutionof an alkyl halide, α-haloketone, or α-haloamide in an organic solventat about 0° C. The reaction mixture is stirred at about −10° C. toambient temperature (preferably ambient temperature) for about 0.5-24 h(preferably about 1 h). Optionally, the organic solvent may be removedunder reduced pressure. Optionally, the reaction mixture or residue maybe diluted with water, aqueous NH₄Cl, or aqueous NaHCO₃. If aprecipitate forms the solid may be optionally collected via vacuumfiltration to give the target compound. Alternatively, an organicsolvent (such as EtOAc or DCM) is added to the aqueous mixture and thelayers are separated. The aqueous layer may optionally be extractedfurther with an organic solvent (such as EtOAc and/or DCM). The combinedorganic layers are optionally washed with additional aqueous solutionssuch as brine, dried over anhydrous Na₂SO₄ or MgSO₄, filtered, andconcentrated to dryness under reduced pressure.

Illustration of General Procedure S.1 Preparation #S.1.1 tert-butyl2-amino-2-oxoethyl(5-tosyl-5H-pyrrolo[3,2-b]pyrazin-2-yl)carbamate

To a solution of tert-butyl5-tosyl-5H-pyrrolo[3,2-b]pyrazin-2-ylcarbamate (1.00 g, 2.57 mmol,Example #3 Step E) and DMF (13 mL) under nitrogen at about 0° C. wasadded NaH (60% dispersion in mineral oil, 0.113 g, 2.83 mmol) in oneportion. After about 30 min, 2-bromoacetamide (0.391 g, 2.83 mmol) wasadded in one portion. After about 30 min, the ice bath was removed andthe solution was stirred at ambient temperature for about 2 h. Saturatedaqueous NH₄Cl/water (1:1, 100 mL) was added. After stirring for about 10min, the mixture was filtered using water to wash the filter cake. Theaqueous phase was extracted with EtOAc (50 mL). The filter cake wasdissolved in EtOAc and added to the organic layer. The organic layer wasdried over Na₂SO₄, filtered, and concentrated under reduced pressure.The material was purified by silica gel chromatography eluting with agradient of 20-100% EtOAc/heptane to give tert-butyl2-amino-2-oxoethyl(5-tosyl-5H-pyrrolo[3,2-b]pyrazin-2-yl)carbamate(0.980 g, 82%): LC/MS (Table 1, Method n) R_(t)=0.70 min; MS m/z 446(M+H)⁺.

General Procedure T: Cyclization of a Ketone Using a DithiaphosphetaneReagent

To a solution of a ketone (preferably 1 equiv) in an organic solventsuch as THF or 1,4-dioxane (preferably 1,4-dioxane) is added athiolating reagent such as Lawesson's reagent or Belleau's reagent(2,4-bis(4-phenoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide)(0.5-2.0 equiv, preferably Lawesson's reagent, 0.5-0.6 equiv). Thereaction is heated at about 30° C. to 120° C. (preferably about 60-70°C.) for about 0.5-10 h (preferably about 1-2 h). Optionally, additionalthiolating reagent (0.5-2.0 equiv, preferably 0.5-0.6 equiv) can beadded to the reaction mixture and heating can be continued for about0.5-10 h (preferably about 1-2 h). The reaction mixture is concd underreduced pressure.

Illustration of General Procedure T Preparation #T.1N,N-dibenzyl-3-methyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentanamine

A mixture of1-(4-(dibenzylamino)-2-methylcyclopentyl)-2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)ethanone(5.32 g, 8.75 mmol, Preparation #50) and Lawesson's reagent (1.88 g,4.64 mmol) in 1,4-dioxane (60 mL) was heated at about 60° C. for about 2h. Lawesson's reagent (1.88 g, 4.64 mmol) was added and stirring atabout 60° C. was continued for about 1 h. The solvent was removed andthe residue subjected to silica gel flash chromatography eluting with agradient of 0-8% MeOH in DCM to yieldN,N-dibenzyl-3-methyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentanamine(4.47 g, 87%) as a brown amorphous solid: LC/MS (Table 1, Method a)R_(t)=2.99 min; MS m/z 590 (M+H)⁺.

General Procedure U: Knoevenagel Condensation to Form a SubstitutedCyclopentadiene

A round bottom flask is charged with an organic solvent (for example THFor diethylene glycol dimethyl ether; preferably THF), followed by theportionwise addition of NaH (60% dispersion in mineral oil, preferably 1equiv). An organic solvent can optionally be added. The reaction mixtureis cooled to about 15-5° C. (preferably about −10-0° C.). A β-keto ester(preferably 1 equiv) is added dropwise at a rate to keep the internaltemperature below about 10° C. The resulting mixture is stirred at about0-60° C. (preferably about 25° C.) for about 0.1-2 h (preferably about0.5 h), followed by dropwise addition of an appropriately substitutedα-haloketone (preferably 0.45-0.55 equiv). The resulting mixture isheated to about 40-80° C. (preferably about 50° C.) for about 3-24 h(preferably about 19 h). The organic solvent is removed under reducedpressure and the resulting crude material is stirred with water whilecooling in an ice bath. The resulting suspension is filtered after about0.5-3 h (preferably about 2 h) and the filter cake is washed with waterand dried under vacuum for about 1-3 h (preferably about 1 h). Theresulting solid is suspended in an organic solvent (preferably Et₂O),collected by vacuum filtration, washed with an organic solvent(preferably Et₂O), and dried under vacuum to give the desired product asa sodium salt of the enolate. Optionally, toluene is added and the wateris azetroped. The resulting solid is re-suspended in an organic solvent(preferably Et₂O), collected by vacuum filtration, washed with anorganic solvent (preferably Et₂O), and then dried under vacuum.

Illustration of General Procedure U Preparation #U.1 sodium4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-dienolate

A round bottom flask was charged with THF (1.5 L) followed by theportionwise addition of NaH (60% dispersion in mineral oil, 70.0 g, 1.75mol). Additional THF (500 mL) was added and the resulting mixture wascooled to about −10° C. Ethyl propionylacetate (250 mL, 1.80 mol) wasadded dropwise over about 1 h in order to keep internal temperaturebelow about 10° C. The resulting mixture was stirred at ambienttemperature for about 0.5 h to give a clear yellow solution and thenmethyl 4-chloroacetoacetate (100 mL, 0.88 mol) was added dropwise overabout 5 min. The resulting mixture was heated at about 50° C. for about19 h to give a reddish orange suspension. The reaction mixture wascooled to ambient temperature, concd under reduced pressure and theresulting liquid was transferred to a beaker and diluted with water (350mL). The mixture was stirred in an ice bath for about 2 h. The solid wascollected by vacuum filtration and the filter cake was rinsed with water(150 mL) and dried under vacuum for about 1 h. The solid was suspendedin Et₂O (1.5 L), filtered, washed with Et₂O (1.5 L), and dried undervacuum. The resulting solid was azeotroped with toluene (1 L) to give asolid that was re-suspended in Et₂O (1 L) and collected by vacuumfiltration. The filter cake was washed with Et₂O (500 mL) and driedunder vacuum to give sodium4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-dienolate(204.2 g, 89%) as beige solid: ¹H NMR (DMSO-d₆) δ 3.94 (q, J=7.1 Hz,2H), 3.46 (s, 3H), 3.04 (q, J=7.2 Hz, 2H), 2.66 (s, 2H), 1.13 (t, J=7.1Hz, 3H), 0.99 (t, J=7.3 Hz, 3H).

General Procedure V: Decarboxylation of a β-Ketoester Enolate

A round bottom flask is charged with an appropriate β-keto ester or itssodium enolate (preferably 1 equiv), an organic solvent (for examplediethylene glycol dimethyl ether or toluene, preferably toluene), AcOH(2-5 equiv, preferably 3.5 equiv), NaI or KCl (1-5 equiv, preferably1.4-1.5 equiv of KCl) with or without water (preferably with water). Thereaction is heated to reflux for about 1-10 h (preferably about 3-6 h).The reaction is cooled to ambient temperature and is added dropwise intoaqueous NaHCO₃ (preferably 8-10% NaHCO₃). The resulting mixture isextracted with an organic solvent such as Et₂O or MTBE (preferablyMTBE). The combined organic layers are dried over anhydrous Na₂SO₄ orMgSO₄, filtered, and concd to dryness under reduced pressure.

Illustration of General Procedure V Preparation #V.1 ethyl2-ethyl-4-oxocyclopent-2-enecarboxylate

A 5 liter round bottom flask was charged with sodium4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-dienolate(316 g, 1205 mmol, Preparation #U.1), KCl (126 g, 1687 mmol, JT-Baker),AcOH (241 mL, 4218 mmol, JT-Baker), toluene (1850 mL) and water (130mL). The reaction was heated at reflux for about 6 h then cooled toambient temperature and added dropwise to 8% aqueous NaHCO₃ (3.5 L). Theresulting biphasic mixture was extracted with MTBE (2×1.5 L). Thecombined organic layers were washed with brine (1 L), dried overanhydrous MgSO₄ and concd under reduced pressure to give 191 g of crudematerial that was purified by vacuum distillation (97-99° C., 0.600 mmHg) to give ethyl 2-ethyl-4-oxocyclopent-2-enecarboxylate (160 g, 69%):¹H NMR (CDCl₃) δ 6.04 (m, 1H), 4.26-4.15 (m, 2H), 3.76-3.69 (m, 1H),2.75-2.57 (m, 2H), 2.56-2.44 (m, 2H), 1.32-1.26 (m, 3H), 1.23-1.18 (m,3H).

General Procedure W: Hydrogenation of an Alkene

A round bottom flask is charged with 10 wt % Pd/C (about 0.005-0.05equiv, preferably 0.02 equiv). The flask is evacuated then flushed withnitrogen 2-5 times (preferably 3 times), then is optionally cooled toabout −10-10° C. (preferably about 0° C.) prior to addition of anorganic solvent or mixture of solvents (such as EtOAc, MeOH, EtOH orMeOH/AcOH, preferably EtOAc or MeOH) under a nitrogen atmosphere. Thecooling bath is removed and to the mixture is added an alkene(preferably 1 equiv) neat or optionally as a solution in an organicsolvent or mixture of solvents (such as EtOAc, MeOH, EtOH or MeOH/AcOH,preferably EtOAc or MeOH). Hydrogen gas is bubbled through the reactionmixture for about 1-20 min (preferably about 5 min) and the mixture isstirred under a hydrogen atmosphere for about 12-60 h (preferably about48 h). In cases where the reaction does not proceed to completion asmonitored by TLC, LC/MS, or HPLC, the hydrogen source is removed, thereaction mixture is bubbled with nitrogen for about 1-20 min (preferablyabout 5 min) and then filtered through a pad of Celite®, and thefiltrate is concd under reduced pressure. The crude material isresubjected to the previously described reaction conditions for about2-20 h (preferably about 5 h). The hydrogen source is removed and themixture is bubbled with nitrogen for about 1-20 min (preferably about 5min) and then filtered through a pad of Celite®. The filter cake isrinsed with an organic solvent (such as EtOAc, MeOH or EtOH, preferablythe reaction solvent) and the filtrate is concd under reduced pressureto give the crude product.

Illustration of General Procedure W Preparation #W.1 ethyl2-ethyl-4-oxocyclopentanecarboxylate

A round bottom flask was charged with 10 wt % Pd/C (10 g, 9.4 mmol). Theflask was cooled to about 0° C. and EtOAc (400 mL) was added under anitrogen atmosphere. The cooling bath was removed and ethyl2-ethyl-4-oxocyclopent-2-enecarboxylate (47.8 g, 263 mmol, Preparation#V.1) was added. Hydrogen gas was bubbled through the mixture for about5 min and the mixture was then stirred under a hydrogen atmosphere forabout 48 h. The hydrogen source was removed and the mixture was bubbledwith nitrogen for about 5 min and was filtered through a pad of Celite®.The filter cake was rinsed with EtOAc (400 mL). The filtrate was concdunder reduced pressure to give ethyl2-ethyl-4-oxocyclopentanecarboxylate (about 9:1 mixture cis: trans)(48.0 g, 99%) as a yellow liquid: ¹H NMR (CDCl₃) δ 4.23-4.10 (m, 2H),3.22 (m, 1H), 2.59-2.50 (m, 1H), 2.44-2.28 (m, 3H), 2.26-2.16 (m, 1H),1.58-1.46 (m, 1H), 1.41-1.30 (m, 1H), 1.30-1.23 (m, 3H), 1.02-0.91 (m,3H).

TABLE W.1 Examples prepared with General Procedure W R_(t) min (Table 1,m/z ESI+ Alkene Product Ex. # Method) (M + H)⁺N-(4-(3-allyl-6H-imidazo[1,5- a]pyrrolo[2,3-e]pyrazin-1-yl)bicyclo[2.2.2]octan-1- yl)cyclopropanesulfonamide (Example #D.1.40)

W.1.1 1.95 (a) 428 2-((3R,4S)-3-ethyl-4-(6H- pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentylidene)acetic acid(prepared from Preparation #25 using III with triethyl phosphonoacetate,Z with NaOH, D with NaOH)

W.1.2 1.47 314

General Procedure W.1: Hydrogenation of an Alkene

A round bottom flask is charged with a slurry of Pd(OH)₂ on carbon orPd/C (about 0.005-0.10 equiv, preferably 0.05 equiv) in an organicsolvent or mixture of solvents (such as THF, EtOAc, MeOH, EtOH orMeOH/AcOH, preferably THF) under a nitrogen atmosphere. The mixture isadded to an alkene (preferably 1 equiv) neat or optionally as a solutionin an organic solvent or mixture of solvents (such as THF, EtOAc, MeOH,EtOH or MeOH/AcOH, preferably THF) or optionally the alkene is added tothe Pd mixture. The reaction mixture is sparged with hydrogen. Themixture is stirred or shaken (preferably stirred when atmospherichydrogen is used or shaken when higher pressures of hydrogen is used)under hydrogen at about atmospheric pressure 60 psi (preferablyatmospheric pressure) at about 20-60° C. (preferably ambienttemperature) for about 0.5-5 days (preferably about 3 days). Thereaction mixture is filtered through a pad of Celite®. The filter cakeis rinsed with an organic solvent (such as THF, EtOAc, DCM, MeOH, orEtOH, preferably the reaction solvent) and the filtrate is concd underreduced pressure to give the crude product.

Illustration of General Procedure W.1 Preparation #W.1.1 and W.1.2 ethyl2-((1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)acetateand2-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)acetate

To a slurry of 20 wt % Pd(OH)₂ on carbon (0.134 g, 0.192 mmol) in THF(20 mL) was added a solution of (E)-ethyl2-((cis)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylidene)acetate(1.3 g, 3.83 mmol, Example #38, Step G) in THF (5 mL). The reactionmixture was sparged with hydrogen and an atmosphere of hydrogen wasmaintained via balloon. After about 3 days, the reaction mixture wasfiltered through Celite®, concd under reduced pressure and purified byflash chromatography on silica gel eluting with EtOAc to afford a darkbrown/black solid. The compound was further by purified by chiralchromatography (Table 2, Method 47) to afford ethyl2-((1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)acetate[W.1.1] (R_(t)=12.0 min, or =negative) (0.400 g, 31%): LC/MS (Table 1,Method a) R_(t)=1.85 min; MS m/z: 342 (M+H)⁺ and ethyl2-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)acetate[W.1.2] (R_(t)=13.7 min, or =negative) (0.420 g, 32%) as a white solid:LC/MS (Table 1, Method a) R_(t)=1.85 min; MS m/z: 342 (M+H)⁺.

General Procedure X: Reductive Amination of a Ketone or Aldehyde

A round bottom flask is charged with a ketone or an aldehyde (1-40equiv; preferably 1 equiv) in an organic solvent (such as DCE, MeCN,MeOH, or MeCN/MeOH; preferably DCE). The mixture is optionally cooled toabout −10-10° C. (preferably about 0° C.) and AcOH (1-3 equiv;preferably 1.5 equiv) and an amine (1-3 equiv, preferably 1 equiv) areadded dropwise, followed by the portionwise addition of a suitablereducing agent such as NaBH(OAc)₃, Na(CN)BH₃, NaBH₄, preferablyNaBH(OAc)₃ (1-6 equiv, preferably 1.5 equiv). Alternatively, to asolution of an amine (1-3 equiv, preferably 1 equiv) in an organicsolvent (such as DCE, MeCN, or MeOH; preferably DCE) is added a ketoneor an aldehyde (1-40 equiv; preferably 1 equiv) followed by subsequentportionwise addition of an appropriate reducing agent such asNaBH(OAc)₃, Na(CN)BH₃, NaBH₄, preferably NaBH(OAc)₃ (1-6 equiv,preferably 1.5 equiv). The mixture is stirred for about 5-20 min(preferably about 15 min) followed by the dropwise addition of AcOH (1-3equiv; preferably 1.5 equiv). If the reaction mixture becomes tooviscous to stir freely, additional organic solvent (such as DCE, MeCN,MeOH, or MeCN/MeOH mixture; preferably DCE) is optionally added to aidstirring. The reaction mixture is stirred at ambient temperature forabout 1-48 h (preferably about 20 h). The reaction mixture is slowlypoured into a solution of aqueous base (such as saturated aqueousNaHCO₃) followed by optional addition of solid NaHCO₃ and stirred forabout 0.5-3 h (preferably about 2 h). The layers are separated and theorganic solution is dried over anhydrous Na₂SO₄ or MgSO₄, filtered, andconcd to dryness under reduced pressure.

Illustration of General Procedure X Preparation #X.1 ethyl4-(dibenzylamino)-2-ethylcyclopentanecarboxylate

A round bottom flask was charged with ethyl2-ethyl-4-oxocyclopentanecarboxylate (95.9 g, 521 mmol, Preparation#W.1) and DCE (1.8 L). The solution was cooled to about 0° C. and AcOH(45 mL, 780 mmol) and dibenzylamine (120 mL, 625 mmol) were addeddropwise, resulting in formation of a thick suspension. The reactionmixture was warmed to about 10° C. and additional DCE (500 mL) wasadded. NaBH(OAc)₃ (166 g, 781 mmol) was added portionwise and thereaction mixture was stirred at ambient temperature for about 20 h. Thereaction mixture was slowly poured into stirred saturated aqueous NaHCO₃(1.5 L), followed by the portionwise addition of solid NaHCO₃ (175 g).The mixture was stirred for about 2 h and the organic layer wasseparated, dried over anhydrous Na₂SO₄, and concd to dryness underreduced pressure. The crude yellow oil was purified by silica gelchromatography eluting with 0-20% EtOAc in heptane to yield ethyl4-(dibenzylamino)-2-ethylcyclopentanecarboxylate (136.6 g, 72%) as awhite solid: LC/MS (Table 1, Method a) R_(t)=3.26 min; MS m/z: 366(M+H)⁺

TABLE X.1 Examples prepared from 1-((3R,4R)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine hydrochloride (Example #5, StepJ) using General Procedure X with NaBH₃CN Ex- R_(t) min ample (Table 1,m/z ESI+ Aldehyde Product # Method) (M + H)⁺ Benz- aldehyde

X.1.1* 1.51 (b) 346

TABLE X.2 Examples prepared from acetaldehyde using General Procedure Xwith NaBH₃CN R_(t) min (Table 1, m/z ESI+ Amine Product Example #Method) (M + H)⁺ (trans)-4-(3H-imidazo[1,2- a]pyrrolo[2,3-e]pyrazin-8-yl)cyclohexanamine (Example #F.1.2)

X.2.1 0.97 (a) 312

TABLE X.3 Examples prepared from 4,4,4-trifluorobutyraldehyde [Matrix]using General Procedure X with Na(OAc)₃BH R_(t) min (Table 1, m/z ESI+Amine Product Example # Method) (M + H)⁺ (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin- 1-yl)cyclopentanamine(Preparation #44)

X.3.1 1.90 (a) 491

TABLE X.4 Examples prepared from(3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanone (prepared using D from Preparation #25using D), and General Procedure X with Na(OAc)₃BH R_(t) min (Table 1,m/z ESI+ Amine Product Example # Method) (M + H)⁺ oxetan-3-amine[Synthonix]

X.4.1 1.01 (a) 327 3-methyloxetan-3-amine [Synthonix]

X.4.2 1.06 (a) 341

General Procedure X.1: Reductive Amination of a Ketone or Aldehyde

A ketone or an aldehyde (1-40 equiv; preferably 1 equiv) is optionallydissolved or slurried in an organic solvent or solvents such as DCE,MeCN, MeOH, MeCN/MeOH, EtOH, THF, DMF, AcOH, or DCM (preferably DCE).The mixture is optionally cooled to about −10-10° C. (preferably about0° C.). Optionally, AcOH (1-3 equiv; preferably 1.5 equiv) is added. Anamine (1-3 equiv, preferably 1 equiv) is added neat or as a solution inan organic solvent or solvents such as DCE, MeCN, MeOH, EtOH, THF, DMF,AcOH, or DCM (preferably DCE). Alternatively, a ketone or aldehyde orsolution of ketone or aldehyde may be added to an amine or aminesolution. A dehydrating reagent such as molecular sieves or titanium(IV)tetraisopropoxide may optionally be added or water may be removed usinga Dean-Stark trap. The solvent is optionally removed under reducedpressure and an organic solvent or solvents such as DCE, MeCN, MeOH,EtOH, THF, DMF, AcOH, or DCM may be added. After stirring for about 5min-24 h (preferably 15 min) at 0° C. to 100° C. (preferably ambienttemperature), a suitable reducing agent such as NaBH(OAc)₃, Na(CN)BH₃,NaBH₄, preferably NaBH(OAc)₃ (1-10 equiv, preferably 1.5 equiv) is addedportionwise. If the reaction mixture becomes too viscous to stir freely,additional organic solvent is optionally added to aid stirring. Thereaction mixture is stirred at ambient temperature for about 1-72 h(preferably about 20 h). Optionally, the reaction mixture may be treatedwith water and then filtered or the volatiles may be removed underreduced pressure. The reaction mixture is slowly poured into a solutionof aqueous base, water, or aqueous acid (preferably saturated aqueousNaHCO₃) or alternatively the aqueous solution is slowly added to thereaction mixture. Optionally, additional solid NaHCO₃ may be added. Themixture is vigorously stirred for about 0.5-20 h (preferably about 2 h).The layers are separated and the organic solution is dried overanhydrous Na₂SO₄ or MgSO₄, filtered, and concentrated to dryness underreduced pressure.

Illustration of General Procedure X.1 Preparation #X.1.1 tert-butyl(trans-4-((6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-8-yl)methylamino)cyclohexyl)methylcarbamate

tert-Butyl trans-4-aminocyclohexylmethylcarbamate (0.059 g, 0.258 mmol,AMRI) was added to a mixture of6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-8-carbaldehyde (0.0403g, 0.215 mmol, Preparation #38) and THF (1.0 mL). The mixture wasstirred at ambient temperature for about 90 min. Sodiumtriacetoxyborohydride (0.068 g, 0.32 mmol) was added. After about 3 h,DMF (0.500 mL) was added. After about 15 h, Na(OAc)₃BH (0.091 g, 0.43mmol) was added. After about 24 h, Na(OAc)₃BH (0.091 g, 0.43 mmol) wasadded. The mixture was warmed to about 40° C. After about 22 h, themixture was allowed to cool to ambient temperature. Saturated aqueousNaHCO₃/water (1:1, 2 mL) was added. After vigorously stirring for about1 h, the solution was diluted with water (3 mL) and then extracted withEtOAc (6×10 mL). The combined organics were dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The residue was purified silicagel chromatography eluting with a gradient of 10-100% [(1% 7 N NH₃ inMeOH) in 10% MeOH/DCM]/DCM to give tert-butyl(trans-4-((6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-8-yl)methylamino)cyclohexyl)methylcarbamate(0.0476 g, 53%): LC/MS (Table 1, Method a) R_(t)=1.24 min; MS m/z 400(M+H)⁺.

General Procedure Y: Hydrogenation of a Benzyl- or Cbz-Protected Amine

To a vessel charged with a benzyl- or Cbz-protected amine (preferably 1equiv) was added a palladium catalyst (for example Pd(OH)₂ on C or Pd/C;preferably Pd(OH)₂ on C) (0.01-0.2 equiv, preferably 0.02-0.15 equiv)and an organic solvent (such as MeOH or EtOH, preferably EtOH). Themixture is shaken or stirred at about 25-60° C. (preferably about 50°C.) for about 1-96 h (preferably about 1.5-3 h) at about 15-60 psihydrogen (preferably about 30-50 psi hydrogen). In cases where thereaction does not proceed to completion as monitored by TLC, LC/MS, orHPLC, the hydrogen source is removed, the reaction mixture is bubbledwith nitrogen for about 5-20 min (preferably about 5 min) and thenfiltered through a pad of Celite®, and the filtrate is concd underreduced pressure. The crude material is resubjected to the previouslydescribed reaction conditions for about 2-20 h (preferably about 3-5 h).When the reaction is complete as monitored by TLC, LC/MS, or HPLC, thehydrogen source is removed, a nitrogen atmosphere is introduced, and thereaction mixture is filtered through a pad of Celite®. The filtrate isconcd under reduced pressure to give the desired product.

Illustration of General Procedure Y Preparation #Y.1 ethyl4-amino-2-ethylcyclopentanecarboxylate

To a vessel containing a slurry of 20 wt % Pd(OH)₂ on C (12.9 g, 18.4mmol) in EtOH (1.0 L) was added ethyl4-(dibenzylamino)-2-ethylcyclopentanecarboxylate (129 g, 352 mmol,Preparation #X.1). The reaction was shaken for about 90 min at about 50°C. under about 30 psi of hydrogen. After removal of the hydrogen sourceand introduction of a nitrogen atmosphere, the resulting mixture wasfiltered through a pad of Celite® and the filtrate was concd underreduced pressure to give ethyl 4-amino-2-ethylcyclopentanecarboxylate(64.5 g, 99%) as a yellow syrup: ¹H NMR (CDCl₃) δ 4.03-3.88 (m, 2H),3.17 (m, 1H), 2.68 (m, 1H), 2.09-2.02 (m, 2H), 2.02-1.94 (m, 2H), 1.84(m, 1H), 1.58-1.48 (m, 1H), 1.32-1.18 (m, 1H), 1.09 (m, 3H), 1.03 (m,2H), 0.78-0.69 (m, 3H).

TABLE Y.1 Examples prepared using General Procedure Y R_(t) min (Table1, m/z ESI+ Dibenzyl amine Product Ex # Method) (M + H)⁺trans-1-(4-(3H-imidazo[1,2- a]pyrrolo[2,3-e]pyrazin-8-yl)cyclohexyl)-N,N- dibenzylmethanamine (prepared using S from methyl 4-(aminomethyl)cyclohexanecarboxylate [prepared as described in Molecules2008, 13, 1111-1119] and benzyl bromide, Z with NaOH, R, S with Example#3 Step E, E with TFA, KKKK with PFPAA, D with NaOH)

Y.1.x 1.27 (a) 270

General Procedure Z: Basic Hydrolysis of an Ester to a Carboxylic Acid

To a flask containing an ester (preferably 1 equiv) either neat or in anorganic solvent (such as 1,4-dioxane, MeOH, or THF/MeOH, preferably1,4-dioxane) is added an aqueous base (such as aqueous NaOH or LiOH,1-10 equiv, preferably 2-6 equiv). The mixture is stirred at about0-100° C. (preferably ambient temperature) for about 1-48 h (preferablyabout 4-8 h). The reaction mixture is then acidified by the addition ofa suitable aqueous acid (such as aqueous HCl). The layers are separatedand the aqueous layer is optionally extracted with additional organicsolvent (such as EtOAc or DCM, preferably DCM). The organic layer orlayers are optionally dried over anhydrous Na₂SO₄ or MgSO₄, filtered,and concd to dryness under reduced pressure to give crude targetcompound. Alternatively, the reaction mixture is concd under reducedpressure to give crude target compound as a carboxylate salt.

Illustration of General Procedure Z Preparation #Z.1*(1S4R,4S)-4-(cyclopropanesulfonamido)-2-ethylcyclopentanecarboxylic acid

To a flask containing (1S,2R,4S)-ethyl4-(cyclopropanesulfonamido)-2-ethylcyclopentane-carboxylate (11.1 g,38.4 mmol, prepared using K from Preparation #Y.1, cyclopropanesulfonylchloride and TEA, AA [Table 2, Method 1, R_(t)=9.5 min, or =negative])was added aqueous NaOH (1 N, 210 mL, 210 mmol). After stirring atambient temperature for about 8 h, the reaction was acidified to aboutpH 1 using 6 N aqueous HCl and extracted with DCM (3×150 mL). Thecombined organic layers were washed with brine, dried over anhydrousMgSO₄, filtered, and concd under reduced pressure to give(1S,2R,4S)-4-(cyclopropanesulfonamido)-2-ethylcyclopentanecarboxylicacid with 25 mol % DCM as an excipient (10.7 g, 99%): LC/MS (Table 1,Method a) R_(t)=1.71 min; MS m/z: 260 (M−H)⁻.

General Procedure AA: Chiral Preparative HPLC Purification

Chiral purification is performed using Varian 218 LC pumps, a Varian CVM500 with switching valves and heaters for automatic solvent, column andtemperature control and a Varian 701 Fraction collector. Detectionmethods include a Varian 210 variable wavelength detector, an in-linepolarimeter (PDR-chiral advanced laser polarimeter, model ALP2002) usedto measure qualitative optical rotation (+/−) and an evaporative lightscattering detector (ELSD) (a PS-ELS 2100 (Polymer Laboratories)) usinga 100:1 split flow. ELSD settings are as follows: evaporator: 46° C.,nebulizer: 24° C. and gas flow: 1.1 SLM. The absolute stereochemistry ofthe purified compounds was assigned arbitrarily and is drawn as such.Compounds of the invention where the absolute stereochemistry has beendetermined by the use of a commercially available enantiomerically purestarting material, or a stereochemically defined intermediate, or X-raydiffraction are denoted by an asterisk after the example number.

Illustration of General Procedure AA Examples #AA.1.1 and AA.1.23-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-(trifluoromethyl)piperidin-1-yl)-3-oxopropanenitrileand3-((3S,4S)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-(trifluoromethyl)piperidin-1-yl)-3-oxopropanenitrile

A mixture of3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-(trifluoromethyl)piperidin-1-yl)-3-oxopropanenitrile(0.067 g, 0.18 mmol, prepared using 0 from 4-(trifluoromethyl)nicotinicacid, N, H with Example #5, Step C, HATU and DIEA, Q with Lawesson'sreagent and mercury (II) trifluoroacetate, D with NaOH, F, H with2-cyanoacetic acid, HATU, and DIEA) was dissolved in DMSO:MeOH (2:1, 3mL). The mixture was separated using Varian 218 LC pumps, a Varian CVM500 with switching valves and heaters for automatic solvent, column andtemperature control and a Varian 701 Fraction collector using Method 4(Table 2) to give3-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-(trifluoromethyl)piperidin-1-yl)-3-oxopropanenitrile(R_(t)=12.2 min, or =positive) (0.0284 g, 15%) [AA.1.1] and3-((3S,4S)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-(trifluoromethyl)piperidin-1-yl)-3-oxopropanenitrile(R_(t)=5.3 min, or =negative) (0.0282 g, 15%) [AA.1.2]: LC/MS (Table 1,Method b) R_(t)=1.55 min; MS m/z: 377 (M+H)⁺.

TABLE AA.1 Examples prepared using General Procedure AA StereoisomersR_(t) min m/z ESI+ [Chiral Separation Method] Structure Ex. # (method)(M + H)⁺ 4-((1R,3R)-3-(6H-imidazo[1,5- a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentylamino)benzonitrile and 4-((1R,3S)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1- yl)cyclopentylamino)benzonitrile (preparedusing H from Example #5, Step C and (1R,3R)-3-(tert-butoxycarbonylamino)cyclopentane carboxylic acid [Acros], HATU and DIEA;Q with Lawesson's reagent and mercury (II) trifluoroacetate; E with HCl;PP from 4- cyanophenylboronic acid; D with NaOH) [Table 2, Method 18,R_(t) = 14.5 min, or = ND]

AA.1.3* 1.84 (b) 343 N-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)-(cyclopentyl)cyclopropanesulfonamide (prepared using A from Example #1,Step D and Preparation #Z.1 with HATU and TEA, B with TEA, D with NaOH)[Table 2, Method 2, R_(t) = 10.4 min, or = negative]

AA.1.4* 1.76 (a) 375 N-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)-cyclopentyl)cyclopropanesulfonamide (prepared using A from Example #1,Step D and Preparation #Z.1 with HATU and TEA, B with TEA, D with NaOH)[Table 2, Method 2, R_(t) = 11.3 min, or = positive]

AA.1.5* 1.86 (a) 375 (3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidin-1-yl)(3,3- difluoroazetidin-1-yl)methanone(prepared using J from Example #3, Step G and 3,3-difluoroazetidinehydrochloride with CDI) [Table 2, Method 12, R_(t) = 11.4 min, or =positive]

AA.1.6* 1.58(b)  361 (3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidin-1-yl)(3,3- difluoroazetidin-1-yl)methanone(prepared using J from Example #3, Step G and 3,3-difluoroazetidinehydrochloride with CDI) [Table 2, Method 12, R_(t) = 7.4 min, or =negative]

AA.1.7* 1.58 (b) 361 (3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidin-1-yl)(3,3- difluoropyrrolidin-1-yl)methanone(prepared using J from Example #3, Step G and 3,3-difluoropyrrolidinehydrochloride with CDI) [Table 2, Method 8, R_(t) = 11.5 min, or =positive]

AA.1.8* 1.64 (b) 375 (3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidin-1-yl)(4,4- difluoropiperidin-1-yl)methanone(prepared using J from Example #3, Step G and 4,4-difluoropiperidinehydrochloride with CDI) [Table 2, Method 13, R_(t) = 15.6 min, or =positive]

AA.1.9* 1.72 (b) 389 (3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidin-1-yl)((R)-2- (trifluoromethyl)pyrrolidin-1-yl)methanone (prepared using J from Example #3, Step G and (R)-2-(trifluoromethyl)pyrrolidine with CDI) [Table 2, Method 9, R_(t) = 10.4min, or = positive]

AA.1.10* 1.87 (b) 407 2-(-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4- methylpiperidin-1-yl)thiazole-5-carbonitrile (prepared using L from Example #5, Step J and 2-chlorothiazole-5-carbonitrile [ArkPharm]) [Table 2, Method 15, R_(t) =13.4 min, or = positive]

AA.1.11* 1.89 (b) 364 1-((R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1- yl)piperidine-1-carbonyl)pyrrolidine-3-carbonitrile (prepared using J from Example #6,Step H and pyrrolidine-3- carbonitrile [Tyger] with CDI) [Table 2,Method 14, R_(t) = 16.9 min, or = positive]

AA.1.12* 1.41 (b) 364 N-(3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4- methylcyclopentyl)-3,3,3-trifluoropropane-1-sulfonamide (prepared using K from Preparation #53and 3,3,3- trifluoropropylsulfonyl chloride [Matrix]) [Table 2, Method9, R_(t) = 14.3 min, or = positive]

AA.1.13 1.79 (a) 416 N-(3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4- methylcyclopentyl)-3,3,3-trifluoropropane-1-sulfonamide (prepared using K from Preparation #53and 3,3,3- trifluoropropylsulfonyl chloride [Matrix]) [Table 2, Method9, R_(t) = 12.4 min, or = positive]

AA.1.14 1.79 (a) 416 N-(3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4- methylcyclopentyl)-3,3,3-trifluoropropane-1-sulfonamide (prepared using K from Preparation #51and 3,3,3- trifluoropropylsulfonyl chloride [Matrix]) [Table 2, Method9, R_(t) = 11.9 min, or = negative]

AA.1.15 1.79 (a) 416 5-(3-(3H-imidazo[1,2-a]pyrrolo[2,3,-e]pyrazin-8-yl)-4- methylcyclopentylamino)pyrazine-2-carbonitrile (prepared using L from Preparation #53 and 2-chloro-5-cyanopyrazine [ArkPharm]) [Table 2, Method 8, R_(t) = 18.6 min, or =negative]

AA.1.16 1.69 (a) 359 5-(3-(3H-imidazo[1,2-a]pyrrolo[2,3,-e]pyrazin-8-yl)-4- methylcyclopentylamino)pyrazine-2-carbonitrile (prepared using L from Preparation #51 and 2-chloro-5-cyanopyrazine [ArkPharm]) [Table 2, Method 8, R_(t) = 14.8 min, or =positive]

AA.1.17 1.69 (a) 359 5-(3-(3H-imidazo[1,2-a]pyrrolo[2,3,-e]pyrazin-8-yl)-4- methylcyclopentylamino)pyrazine-2-carbonitrile (prepared using L from Preparation #53 and 2-chloro-5-cyanopyrazine [ArkPharm]) [Table 2, Method 8, R_(t) = 11.5 min, or =positive]

AA.1.18 1.69 (a) 359 5-(3-(3H-imidazo[1,2-a]pyrrolo[2,3,-e]pyrazin-8-yl)-4- methylcyclopentylamino)pyrazine-2-carbonitrile (prepared using L from Preparation #51 and 2-chloro-5-cyanopyrazine [ArkPharm]) [Table 2, Method 8, R_(t) = 9.5 min, or =negative]

AA.1.19 1.69 (a) 359 6-(3-(3H-imidazo[1,2-a]pyrrolo[2,3,-e]pyrazin-8-yl)piperidin-1- yl)nicotinonitrile (prepared using Lfrom Example #3, Step G and 2- chloro-5-cyanopyridine) [Table 2, Method7, R_(t) = 14.9 min, or = positive]

AA.1.20* 1.81 (a) 344 6-(3-(3H-imidazo[1,2-a]pyrrolo[2,3,-e]pyrazin-8-yl)piperidin-1- yl)nicotinonitrile (prepared using Lfrom Example #3, Step G and 2- chloro-5-cyanopyridine) [Table 2, Method7, R_(t) = 11.9 min, or = negative]

AA.1.21* 1.81 (a) 344 2-(3-(3H-imidazo[1,2- a]pyrrolo[2,3,-e]pyrazin-8-yl)piperidin-1-yl)thiazole-5- carbonitrile (prepared using L fromExample #3, Step G and 2-chloro-5- cyanothiazole [ArkPharm]) [Table 2,Method 5, R_(t) = 12.5 min, or = positive]

AA.1.22* 1.74 (a) 350 2-(3-(3H-imidazo[1,2- a]pyrrolo[2,3,-e]pyrazin-8-yl)piperidin-1-yl)thiazole-5- carbonitrile (prepared using L fromExample #3, Step G and 2-chloro-5- cyanothiazole [ArkPharm]) [Table 2,Method 5, R_(t) = 9.4 min, or = negative]

AA.1.23* 1.74 (a) 350 N-(3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl) cyclopentyl)cyclopropanesulfonamide(prepared using TT from Preparation #X.1 with HCl, R with trimethylsilyldiazomethane, S with Example #3, Step E, E with 4N HCl in 1,4-dioxane, Tusing Lawesson's reagent, D with NaOH, Y with Pd(OH)₂ on C, and K fromcyclopropylsulfonyl chloride) [Table 2, Method 6, R_(t) = 8.2 min, or =negative]

AA.1.24 1.64 (a) 374 N-(3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8- yl)cyclopentyl)cyclopropanesulfon- amide(prepared using TT from Preparation #X.1 with HCl, R with trimethylsilyldiazomethane, S with Example #3, Step E, E with 4N HCl in 1,4-dioxane, Tusing Lawesson's reagent, D with NaOH, Y with Pd(OH)₂ on C, and K fromcyclopropylsulfonyl chloride) [Table 2, Method 6, R_(t) = 13.0 min, or =positive]

AA.1.25 1.64 (a) 374 1-(3-(3H-imidazo[1,2-a]pyrrolo[2,3,-e]pyrazin-8-yl)piperidine-1- carbonyl)cyclopropanecarbonitrile(prepared using H from Example #3, Step G and 1-cyano-1-cyclopropane-carboxylic acid) [Table 2, Method 5, R_(t) = 7.3 min, or =negative]

AA.1.26* 1.46 (a) 335 3-(3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylpiperidin- l-yl)-3-oxopropanenitrile (preparedusing N from Example #5, Step D with N-(benzyloxycarbonyloxy)succinimide, R with trimethylsilyl diazomethane, S with Example #3, StepE, E with 4N HCl in 1,4- dioxane, T using Lawesson's reagent, D withNaOH, Y with Pd/C, and H from cyanoacetic acid, EDC, and DIEA) [Table 2,Method 4, R_(t) = 15.9 min, or = negative]

AA.1.27 1.36 (a) 323 4-(3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentyloxy)-benzonitrile(prepared using II from 4- hydroxybenzonitrile and Preparation #FF.1, Dwith Na₂CO₃) [Table 2, Method 17, R_(t) 20.8 min, or = positive]

AA.1.28 2.12 (b) 373 6-(3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentyloxy)-nicotinonitrile(prepared using II from 6- hydroxynicotino-nitrile and Preparation#FF.1, D with Na₂CO₃) [Table 2, Method 18, R_(t) 14.6 min, or =negative]

AA.1.29 2.07 (b) 374 6-(3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentyloxy)-nicotinonitrile(prepared using II from 6- hydroxynicotino-nitrile and Preparation#FF.1, D with Na₂CO₃) [Table 2, Method 18, R_(t) 16.9 min, or =positive]

AA.1.30 2.04 (b) 374 1-(2-ethyl-4-(4- methoxybenzyloxy)cyclopentyl)-6H-pyrrolo[2,3- e][1,2,4]tazolo[4,3-a]pyrazine (prepared using Z fromPreparation #EE.1, A from Example #1, Step D, HATU, and TEA, B withDIEA, D with Na₂CO₃) [Table 2, Method 19, R_(t) 17.1 min, or = negative]

AA.1.31 2.23 (b) 392 1-(2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazine (preparedusing Z from Preparation #EE.1, A from Example #1, Step D, HATU, andTEA, B with DIEA, D with Na₂CO₃) [Table 2, Method 19, R_(t) 19.1 min, or= positive]

AA.1.32 2.22 (b) 392 5-(3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentyloxy)pyrazine-2-carbonitrile (Preparation #LL.1) [Table 2, Method 20, R_(t) 8.1 min, or= negative]

AA.1.33 2.04 (b) 375 5-(3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentyloxy)pyrazine-2-carbonitrile (Preparation #LL.1) [Table 2, Method 20, R_(t) 13.9 min, or= positive]

AA.1.34 2.04 (b) 375 6-(3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentyloxy)nicotino-nitrilecarbonitrile (prepared using II from 6-hydroxynicotinonitrile andPreparation #FF.1, D with Na₂CO₃) [Table 2, Method 21, R_(t) 10.9 min,or = negative]

AA.1.35 2.03 (b) 374 6-(3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentyloxy)nicotino-nitrilecarbonitrile (prepared using II from 6-hydroxynicotinonitrile andPreparation #FF.1, D with Na₂CO₃) [Table 2, Method 21, R_(t) 7.4 min, or= positive]

AA.1.36 2.02 (b) 374 5-(3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentyloxy)pyrazine-2-carbonitrile (prepared using LL from Preparation #JJ.1) [Table 2, Method22, R_(t) 15.5 min, or = negative]

AA.1.37 1.99 (b) 375 5-(3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentyloxy)pyrazine-2-carbonitrile (prepared using LL from Preparation #JJ.1) [Table 2, Method22, R_(t) 16.4 min, or = positive]

AA.1.38 1.97 (b) 375 N-(1-(6H-imidazo[1,5- a]pyrrolo[2,3-e]pyrazin-1-yl)pyrrolidin-3- yl)cyclopropanesulfonamide (Example #15) [Table 2,Method 16, R_(t) = 15.3 min, or = negative]

AA.1.39 1.42 (a) 347 N-(1-(6H-imidazo[1,5- a]pyrrolo[2,3-e]pyrazin-1-yl)pyrrolidin-3- yl)cyclopropanesulfonamide (Example #15) [Table 2,Method 16, R_(t) = 12.5 min, or = positive]

AA.1.40 1.42 (a) 347 5-((cis-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentyl)methoxy)-pyrazine-2-carbonitrile (prepared using P from Preparation #11 with LAH, JJ with2-chloro-5-cyanopyrazine [ArkPharm], TT with HCl, A from Example #1,Step D, HATU and TEA, B with TEA, D with Na₂CO₃) [Table 2, Method 11,R_(t) = 7.5 min, or = ND]

AA.1.41 1.99 (a) 389 5-((cis-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentyl)methoxy)-pyrazine-2-carbonitrile (prepared using P from Preparation #11 with LAH, JJ with2-chloro-5-cyanopyrazine [ArkPharm], TT with HCl, A from Example #1,Step D, HATU and TEA, B with TEA, D with Na₂CO₃) [Table 2, Method 11,R_(t) = 16.1 min, or = ND]

AA.1.42 1.99 (a) 389 N-(cis-4-ethyl-3-fluoro-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)cyclo-propanesulfonamide (prepared using Z from Preparation #7 with NaOH, Afrom Example #1, Step D, HATU and TEA, B with TEA, D with Na₂CO₃) [Table2, Method 10, R_(t) = 18.3 min, or = negative]

AA.1.43 1.71 (a) 393 N-(cis-4-ethyl-3-fluoro-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)cyclo-propanesulfonamide (prepared using Z from Preparation #7 with NaOH, Afrom Example #1, Step D, HATU and TEA, B with TEA, D with Na₂CO₃) [Table2, Method 10, R_(t) = 14.9 min, or = positive]

AA.1.44 1.74 (a) 393 N-(cis-4-ethyl-3-fluoro-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)cyclo-propanesulfonamide (prepared using Z from Preparation #7 with NaOH, Afrom Example #1, Step D, HATU and TEA, B with TEA, D with Na₂CO₃) [Table2, Method 10, R_(t) = 15.5 min, or = positive]

AA.1.45 1.73 (a) 393 N-(cis-4-ethyl-3-fluoro-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)cyclo-propanesulfonamide (prepared using Z from Preparation #7 with NaOH, Afrom Example #1, Step D, HATU and TEA, B with TEA, D with Na₂CO₃) [Table2, Method 10, R_(t) = 16.5 min, or = negative]

AA.1.46 1.75 (a) 393 1-(cis-4-((azetidin-1- ylsulfonyl)methyl)-2-ethylcyclopentyl)-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazine(prepared usingusing the conditions described in Example #1, Step Ksubstituting azetidine for diethylamine, Z with NaOH, A from Example #1,Step D, HATU and TEA, B with TEA, D with NaOH) [Table 2, Method 27,R_(t) = 14.3 min, racemic]

AA.1.47 1.70 (a) 389 1-(cis-4-((azetidin-1- ylsulfonyl)methyl)-2-ethylcyclopentyl)-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazine(prepared using the conditions described in Example #1, Step Ksubstituting azetidine for diethylamine, Step, Z with NaOH, A fromExample #1, Step D, HATU and TEA, B with TEA, D with NaOH) [Table 2,Method 27, R_(t) = 15.5 min, or = positive]

AA.1.48 1.70 (a) 389 N-(3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4- methylcyclopentyl)aniline (preparedusing TT from Preparation #8 with HCl, H from Example #5, Step C, HATUand TEA, Q with Lawesson's reagent and mercury (II) trifluoroacetate, Dwith NaOH) [Table 2, Method 25, R_(t) = 8.0 min, or = negative]

AA.1.49 2.27 (a) 332 N-(3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4- methylcyclopentyl)aniline (preparedusing TT from Preparation #8 with HCl, H from Example #5, Step C, HATUand TEA, Q with Lawesson's reagent and mercury (II) trifluoroacetate, Dwith NaOH) [Table 2, Method 25, R_(t) = 7.1 min, or = positive]

AA.1.50 2.24 (a) 332 N-(3-methyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentyl)aniline (preparedusing TT from Preparation #8 with HCl, A from Example #1, Step D, HATUand TEA, B with TEA, D with NaOH) [Table 2, Method 19, R_(t) = 17.1 min,or = negative]

AA.1.51 1.99 (a) 333 N-(3-methyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentyl)aniline (preparedusing TT from Preparation #8 with HCl, A from Example #1, Step D, HATUand TEA, B with TEA, D with NaOH) [Table 2, Method 19, R_(t) = 18.7 min,or = positive]

AA.1.52 2.02 (a) 333 3-(cis-4-ethyl-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1- yl)piperidin-1-yl)-3- oxopropanenitrile(prepared using W from Preparation #9 with Pd(OH)₂ on C, TT with HCl, M,H from Example #5, Step C, HATU and DIEA, Q with Lawesson's reagent andmercury (II) trifluoroacetate, D with NaOH, E with HCl, H fromcyanoacetic acid, EDC, and DIEA) [Table 2, Method 26, R_(t) = 8.9 min,or = negative]

AA.1.53 1.73 (a) 337 3-(cis-4-ethyl-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1- yl)piperidin-1-yl)-3- oxopropanenitrile(prepared using W from Preparation #9 with Pd(OH)₂ on C, TT with HCl, M,H from Example #5, Step C, HATU and DIEA, Q with Lawesson's reagent andmercury (II) trifluoroacetate, D with NaOH, E with HCl, H fromcyanoacetic acid, EDC, and DIEA) [Table 2, Method 26, R_(t) = 16.1 min,or = positive]

AA.1.54 1.73 (a) 337 1-(3-(pyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidine-1- carbonyl)cyclopropanecarbonitrile(prepared using Y from Preparation #10 with Pd(OH)₂ on C, H from 1-cyanocyclopropanecarboxylic acid, HATU, and DIEA) [Table 2, Method 10,R_(t) = 18.6 min, or = negative]

AA.1.55 1.81 (a) 335 1-(3-(pyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidine-1- carbonyl)cyclopropanecarbonitrile(prepared using Y from Preparation #10 with Pd(OH)₂ on C, H from 1-cyanocyclopropanecarboxylic acid, HATU, and DIEA) [Table 2, Method 10,R_(t) = 21.6 min, or = positive]

AA.1.56 1.83 (a) 335 1-(-2-ethyl-4-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)cyclopentyl)-6H- pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine prepared using FFF from Example #22 Step D with 2-(tetrahydro-2H-pyran-4- yl)acetaldehyde (Biofine), Z, A with Example #1,Step D, HATU, and TEA, B with TEA, D with NaOH [Table 2, Method 33,R_(t) = 11.2 min, or = negative]

AA.1.57 1.85 (a) 384 1-(-2-ethyl-4-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)cyclopentyl)-6H- pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine prepared using FFF from Example #22 Step D with 2-(tetrahydro-2H-pyran-4- yl)acetaldehyde (Biofine), Z, A with Example #1,Step D, HATU, and TEA, B with TEA, D with NaOH [Table 2, Method 33,R_(t) = 5.2 min, or = negative]

AA.1.58 1.90 (a) 384 3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentanone prepared using Dwith Preparation #25 and NaOH [Table 2, Method 34, R_(t) = 9.7 min, or =negative]

AA.1.59 1.34 (a) 270 N-(((1S,3S)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1- yl)cyclopentyl)methyl)cyclopropanesulfonamide and N-(((1S,3R)-3-(6H- imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1- yl)cyclopentyl)methyl)cyclopropane sulfonamide (preparedusing H from Example #5 Step C and Preparation #M.1, HATU and DIEA; Qwith Lawesson's reagent and mercury (II) trifluoroacetate; K withcyclopropanesulfonyl chloride [Matrix]; D with NaOH) [Table 2, Method21, R_(t) = 9.3 min, or = ND]

AA.1.60* 1.67 (a) 360 N-(((1S,3S)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1- yl)cyclopentyl)methyl)cyclopropanesulfonamide and N-(((1S,3R)-3-(6H- imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1- yl)cyclopentyl)methyl)cyclopropane sulfonamide (preparedusing H from Example #5 Step C and Preparation #M.1, HATU and DIEA; Qwith Lawesson's reagent and mercury (II) trifluoroacetate; K withcyclopropanesulfonyl chloride [Matrix]; D with NaOH) [Table 2, Method21, R_(t) = 11.6 min, or = ND]

AA.1.61* 1.70 (a) 360 N-(((1S,3R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1- yl)cyclopentyl)methyl)-3,3,3-trifluoropropane-1-sulfonamide and N-(((1S,3S)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1- yl)cyclopentyl)methyl)-3,3,3-trifluoropropane-1-sulfonamide (prepared using H from Example #5 Step Cand Preparation #M.1, HATU and DIEA; Q with Lawesson's reagent andmercury (II) trifluoroacetate; K with 3,3,3- trifluoropropylsulfonylchloride [Matrix]; D with NaOH) [Table 2, Method 33, R_(t) = 11.8 min,or = negative]

AA.1.62 * 1.90 (a) 416 N-(((1S,3R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1- yl)cyclopentyl)methyl)-3,3,3-trifluoropropane-1-sulfonamide and N-(((1S,3S)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1- yl)cyclopentyl)methyl)-3,3,3-trifluoropropane-1-sulfonamide (prepared using H from Example #5 Step Cand Preparation #M.1, HATU and DIEA; Q with Lawesson's reagent andmercury (II) trifluoroacetate; K with 3,3,3- trifluoropropylsulfonylchloride [Matrix]; D with NaOH) [Table 2, Method 33, R_(t) = 9 min, or =negative]

AA.1.63 * 1.93 (a) 416 N-((3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentyl)methyl)cyclopropanesulfonamide (prepared using K with Preparation #21 Step C andcyclopropanesulfonyl chloride [Matrix]; QQQ with TFA; A from Example #1Step D, HATU and TEA; B with TEA; D with NaOH [Table 2, Method 5, R_(t)= 5.8 min, or = positive]

AA.1.64 1.61 (a) 389 N-((3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentyl)methyl)cyclopropanesulfonamide (prepared using K with Preparation #21 Step C andcyclopropanesulfonyl chloride [Matrix]; QQQ with TFA; A from Example #1Step D, HATU and TEA; B with TEA; D with NaOH) [Table 2, Method 5, R_(t)= 11.4 min, or = negative]

AA.1.65 1.61 (a) 389 1-(2-ethyl-4-((tetrahydro-2H-pyran-4-yl)methoxy)cyclopentyl)-6H- pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (prepared using FFF from Example 22 Step D andtetrahydro-2H-pyran-4- carbaldehyde [J & W PharmLab]; Z with NaOH; Afrom Example #1 Step D, HATU and TEA; B with TEA; D with NaOH) [Table 2,Method 47, R_(t) = 8.7 min, or = negative]

AA.1.66 1.83 (a) 370 1-(2-ethyl-4-((tetrahydro-2H-pyran-4-yl)methoxy)cyclopentyl)-6H- pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (prepared using FFF from Example #22 Step D andtetrahydro-2H-pyran-4- carbaldehyde [J & W PharmLab]; Z with NaOH; Afrom Example #1 Step D, HATU and TEA; B with TEA; D with NaOH) [Table 2,Method 47, R_(t) = 13.8 min, or = negative]

AA.1.67 1.79 (a) 370 1-(2-ethyl-4-(tetrahydro-2H- thiopyran1,1-dioxide-4- yloxy)cyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (prepared using FFF from Example #22Step D and dihydro-2H- thiopyran-4(3H)-one; LLL with mCPBA; Z with NaOH;A from Example #1 Step D, HATU and TEA; B with DIEA; D with NaOH) [Table2, Method 48, R_(t) = 17.1 min, or = negative]

AA.1.68 1.67 (a) 404 1-(2-ethyl-4-(tetrahydro-2H- thiopyran1,1-dioxide-4- yloxy)cyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (prepared using FFF from Example #22Step D and dihydro-2H- thiopyran-4(3H)-one; LLL with mCPBA; Z with NaOH;A from Example #1 Step D, HATU and TEA; B with DIEA; D with NaOH) [Table2, Method 48, R_(t) = 11.6 min, or = negative]

AA.1.69 1.69 (a) 404 1-(2-ethyl-4-(tetrahydro-2H- thiopyran1,1-dioxide-4- yloxy)cyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (prepared using II from Example 22 StepC with 4-nitrobenzoic acid; SS; W; VV; FFF with dihydro-2H-thiopyran-4(3H)-one; LLL with mCPBA; Z with NaOH; A from Example #1 StepD, HATU and TEA; B with DIEA; D with NaOH) [Table 2, Method 32, R_(t) =17.3 min, or = negative]

AA.1.70 1.66 (a) 404 1-(2-ethyl-4- isopropoxycyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazine (prepared using II fromExample 22 Step C with 4- nitrobenzoic acid; SS; VV; FFF with acetone; Zwith NaOH; A from Example #1 Step D, HATU and TEA; B with DIEA; D withNaOH) [Table 2, Method 28, R_(t) = 7.1 min, or = negative]

AA.1.71 1.85 (a) 314 N-((3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8- yl)cyclopentyl)methyl)-3,3,3-trifluoropropane-1-sulfonamide (prepared using X from Preparation #22Step C with dibenzylamine and NaBH(OAc)₃; TT with HCl; R withtrimethylsilyl diazomethane, S with Example #3 Step E; E with TFA; Tusing Lawesson's reagent; D with NaOH; KK; Y with Pd(OH)₂ on C; K with3,3,3-trifluoropropylsulfonyl chloride [Matrix]; LL with NH₄OH) [Table2, Method 49 R_(t) = 24.9 min then 50, R_(t) = 8.6 min, or = negative]

AA.1.72 1.96 (a) 444 N-((3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8- yl)cyclopentyl)methyl)-3,3,3-trifluoropropane-1- sulfonamide (prepared using X from Preparation #22Step C with dibenzylamine and NaBH(OAc)₃; TT with HCl; R withtrimethylsilyl diazomethane, S with Example #3 Step E; E with TFA; Tusing Lawesson's reagent; D with NaOH; KK; Y with Pd(OH)₂ on C; K with3,3,3-trifluoropropylsulfonyl chloride [Matrix]; LL with NH₄OH) [Table2, Method 49 R_(t) = 15 min then 50 R_(t) = 8.7 min, or = positive]

AA.1.73 1.96 (a) 444 N-((3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8- yl)cyclopentyl)methyl)-3,3,3-trifluoropropane-1-sulfonamide (prepared using X from Preparation #22Step C with dibenzylamine and NaBH(OAc)₃; TT with HCl; R withtrimethylsilyl diazomethane, S with Example #3 Step E; E with TFA; Tusing Lawesson's reagent; D with NaOH; KK; Y with Pd(OH)₂ on C; K with3,3,3-trifluoropropylsulfonyl chloride [Matrix]; LL with NH₄OH) [Table2, Method 49 R_(t) = 20.7 min then 50 R_(t) = 9.5 min, or = positive]

AA.1.74 1.96 (a) 444 N-((3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8- yl)cyclopentyl)methyl)-3,3,3-trifluoropropane-1-sulfonamide (prepared using X from Preparation #22Step C with dibenzylamine and NaBH(OAc)₃; TT with HCl; R withtrimethylsilyl diazomethane, S with Example #3 Step E; E with TFA; Tusing Lawesson's reagent; D with NaOH; KK; Y with Pd(OH)₂ on C; K with3,3,3-trifluoropropylsulfonyl chloride [Matrix]; LL with NH₄OH) [Table2, Method 49 R_(t) = 26.5 min then 50 R_(t) = 9 min, or = negative]

AA.1.75 1.97 (a) 444 N-(3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8- yl)cyclopentyl)-3,3,3-trifluoropropane-1-sulfonamide (prepared using X from Example #22 Step Bwith dibenzylamine, TT with HCl, R with trimethylsilyl diazomethane, Swith Example #3 Step E, E with TFA, T with Lawesson's reagent, D withNaOH, Y, K with 3,3,3-trifluoropropane-1- sulfonyl chloride (Matrix) andDIEA) [Table 2, Method 31, R_(t) = 16.9 min, or = postive]

AA.1.76 1.94 (a) 430 N-(3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8- yl)cyclopentyl)-3,3,3-trifluoropropane-1-sulfonamide (prepared using X from Example #22 Step Bwith dibenzylamine, TT with HCl, R with trimethylsilyl diazomethane, Swith Example #3 Step E, E with TFA, T with Lawesson's reagent, D withNaOH, Y, K with 3,3,3-trifluoropropane-1- sulfonyl chloride (Matrix) andDIEA) [Table 2, Method 31, R_(t) = 24 min, or = negative]

AA.1.77 1.94 (a) 430 N-(3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8- yl)cyclopentyl)cyclopropanesulfon- amide(prepared using X from Example #22 Step B with dibenzylamine, TT withHCl, R with trimethylsilyl diazomethane, S with Example #3 Step E, Ewith TFA, T with Lawesson's reagent, D with NaOH, Y, K withcyclopropanesulfonyl chloride (Matrix) and DIEA) [Table 2, Method 12,R_(t) = 15 min, or = negative]

AA.1.78 1.73 (a) 374 N-(3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8- yl)cyclopentyl)-3,3-difluoroazetidine-1-sulfonamide (prepared from prepared using X fromExample #22 Step B with dibenzylamine, TT with HCl, R withtrimethylsilyl diazomethane, S with Example #3 Step E, E with TFA, Twith Lawesson's reagent, D with NaOH, Y, ZZ, AAA with 3,3-difluoroazetidine hydrochloride and TEA) [Table 2, Method 40, R_(t) =15.8 min, or = negative]

AA.1.79 1.84 (a) 425 1-(4-(cyclopropylmethoxy)-2-ethylcyclopentyl)-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazine(prepared using FFF from Example #22 Step D andcyclopropanecarboxaldehyde, Z with NaOH, A with Example #1 Step D, HATUand TEA, B with DIEA, D with NaOH) [Table 2, Method 38, R_(t) = 13.1min, or = negative]

AA.1.80 1.90 (a) 326 N-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4- methylcyclopentyl)-2- hydroxyethylamino-1-sulfonamide(prepared using D from Example #25 Step R with NaOH, LL) [Table 2,Method 32, R_(t) = 20.2 min, or = negative]

AA.1.81 1.21 379 N-3-(3H-imidazo[1,2-a]pyrrolo[2,3- e]pyrazin-8-yl)-4-methylcyclopentyl)-2-methyl-2- hydroxypropylamino-1-sulfonamide(prepared using AAA from Example #25 Step R and 2-methyl-2-hydroxypropyl amine, D with NaOH, LL) [Table 2, Method 36, R_(t) = 12.4min, or = negative]

AA.1.82 1.38 407 N-(3-(3H-imidazo[1,2- a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentyl)morpholine-4- sulfonamide (prepared using AAA fromExample #25 Step R and morpholine, LL) [Table 2, Method 37, R_(t) = 16.4min, or = negative]

AA.1.83 1.53 405 N-3-(3H-imidazo[1,2-a]pyrrolo[2,3- e]pyrazin-8-yl)-4-methylcyclopentyl)-3-amino-1-N- methyazetidine-1-sulfonourea (preparedusing AAA from Example #25 Step R and 3-amino-1-N-methyl azetidine, LL)[Table 2, Method 37, R_(t) = 16.9 min, or = negative]

AA.1.84 1.14 404 1-(8-ethyl-1,4- dioxaspiro[4.4]nonan-7-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazine (prepared using D fromPreparation #25 Step D and NaOH) [Table 2, Method 12, R_(t) = 9.9 min,or = negative]

AA.1.85 1.52 (a) 314 3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)-N-(2,2,2-trifluoroethyl)cyclopentanamine (prepared using X from Preparation #25and 2,2,2-trifluoroethanamine, D with NaOH) [Table 2, Method 31, R_(t) =16.9 min, or = negative]

AA.1.86 1.62 (a) 353 1-(4-(3,3-difluoroazetidin-1-yl)-2-ethylcyclopentyl)-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazine(prepared using X from Preparation #25 and 3,3-difluoroazetidinehydrochloride [Matrix], D with NaOH) [Table 2, Method 21, R_(t) = 9.4min, or = negative]

AA.1.87 1.57 (a) 347 1-(4-(3,3-difluoropyrrolidin-1-yl)-2-ethylcyclopentyl)-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazine(prepared using X from Preparation #25 and 3,3-difluoropyrrolidinehydrochloride, D with NaOH) [Table 2, Method 20, R_(t) = 9.5 min, or =negative]

AA.1.88 1.60 (a) 361 1-(4-(4,4-dimethylcyclohexyloxy)-2-ethylcyclopentyl)-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazine(prepared using II from Example #22 Step C with 4-nitrobenzoic acid, SSwith NaOH, VV, FFF with 4,4- dimethylcyclohexanone, Z with NaOH, A withExample #1 Step D, HATU and TEA, B with DIEA, D with NaOH) [Table 2,Method 41, R_(t) = 10.5 min or = negative]

AA.1.89 2.45 (b) 382 1-(4-(cyclopropylmethoxy)-2-ethylcyclopentyl)-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazine(prepared using II from Example #22 Step C with 4-nitrobenzoic acid, SSwith NaOH, VV, FFF with cyclopropanecarboxaldehyde, Z with NaOH, A withExample #1 Step D, HATU and TEA, B with DIEA, D with NaOH) [Table 2,Method 42, R_(t) = 6.8 min, or = negative]

AA.1.90 1.89 (b) 326 1-(2-ethyl-4-(tetrahydro-2H-pyran-4-yloxy)cyclopentyl)-6H- pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazine(prepared using II from Example #22 Step C with 4- nitrobenzoic acid, SSwith NaOH, VV, FFF with tetrahydro-4H-pyran- 4-one, Z with NaOH, A fromExample #1 Step D, HATU and TEA, B with DIEA, D with NaOH) [Table 2,Method 33, R_(t) = 7.6 min, or = negative]

AA.1.91 1.63 (b) 356 3-chloro-N-(3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3- e]pyrazin-8-yl)cyclopentyl)-4-fluorobenzenesulfonamide (prepared using X from Example #22 Step B withdibenzylamine, TT with HCl, R with trimethylsilyl diazomethane, S withExample #3 Step E, E with TFA, T with Lawesson's reagent, D with NaOH,Y, K with 3-chloro-4- fluorobenzenesulfonyl chloride [Lancaster] andDIEA [Table 2, Method 19, R_(t) = 24.2 min, or = negative]

AA.1.92 2.11 (a) 462 4-(3-methyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentyloxy)benzonitril(prepared using P from Example #7, step G, EE with 4-methoxybenzyl-2,2,2-trichloroacetimidate, Z with NaOH, , A with Example #1 Step D,HATU, and TEA, B with DIEA, FF with 2,3-dichloro-5,6-dicyano-p-benzoquinone, II with hydroxybenzonitrile, D with Na₂CO₃) [Table 2,Method 17, R_(t) = 25.7 min, or = positive]

AA.1.93 1.94 (b) 430 4-(3-methyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentyloxy)benzonitrile(prepared using P from Example #7, step G, EE with 4-methoxybenzyl-2,2,2-tchloroacetimidate, Z with NaOH, A with Example #1 Step D, HATU,and TEA, B with DIEA, FF with 2,3-dichloro-5,6-dicyano-p- benzoquinone,II with hydroxybenzonitrile, D with Na₂CO₃) [Table 2, Method 17, R_(t) =14.7 min, or = negative]

AA.1.94 1.94 (b) 430 1-(2-ethyl-4-(5- (trifluoromethyl)pyridin-2-yloxy)cyclopentyl)-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazine(prepared using II from 5- (trifluoromethyl)pyridin-2-ol and Preparation#FF.1, D with NaOH) [Table 2, Method 21, R_(t) = 8 min, or = negative]

AA.1.95 2.33 (b) 417 1-(2-ethyl-4-(5- (trifluoromethyl)pyridin-2-yloxy)cyclopentyl)-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazine(prepared using II from 5- (trifluoromethyl)pyridin-2-ol and Preparation#FF.1, D with NaOH) [Table 2, Method 21, R_(t) = 5.3 min, or = positive]

AA.1.96 2.33 (b) 417 5-(3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentyloxy)pyrazine-2-carbonitrile (prepared using LL from Preparation #JJ.1) [Table 2, Method43, R_(t) = 19.9 min, or = negative]

AA.1.97 1.99 (b) 375 5-(3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentyloxy)pyrazine-2-carbonitrile (prepared using LL from Preparation #JJ.1) [Table 2, Method43, R_(t) = 18.3 min, or = positive]

AA.1.98 2.01 (b) 375 3-((3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentyloxy)methyl)benzonitrile(prepared using JJ from 3- (bromomethyl)benzonitrile and Preparation#SS.1, LL with TFA and ammonium hydroxide) [Table 2, Method 34, R_(t) =11.9 min, or = negative]

AA.1.99 2.05 (b) 387 3-((3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentyloxy)methyl)benzonitrile(prepared using JJ from 3- (bromomethyl)benzonitrile and Preparation#SS.1, LL with TFA and ammonium hydroxide) [Table 2, Method 34, R_(t) =15.1 min, or = positive]

AA.1.100 2.05 (b) 387 4-((3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentyloxy)methyl)benzonitrile(prepared using JJ from 4- (bromomethyl)benzonitrile and Preparation#SS.1, LL with TFA and ammonium hydroxide) [Table 2, Method 34, R_(t) =13.4 min, or = negative]

AA.1.101 2.04 (b) 387 4-((3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentyloxy)methyl)benzonitrile(prepared using JJ from 4- (bromomethyl)benzonitrile and Preparation#SS.1, LL with TFA and ammonium hydroxide) [Table 2, Method 34, R_(t) =16.9 min, or = positive]

AA.1.102 2.04 (b) 387 4-(3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentyloxy)-2-fluorobenzonitrile (prepared using II from 2-fluoro-4-hydroxybenzonitrile and Example #4 Step J, B with DIEA, D with Na₂CO₃)[Table 2, Method 5, R_(t) = 7.7 min, or = negative]

AA.1.103 2.08 (b) 391 4-(3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentyloxy)-3-fluorobenzonitrile (prepared using II from 3-fluoro-4-hydroxybenzonitrile and Example #4 Step J, B with DIEA, D with Na₂CO₃)[Table 2, Method 44, R_(t) = 12.5 min, or = negative]

AA.1.104 2.12 (b) 391 3-(3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentyloxy)benzonitrile(prepared using II from 3- hydroxybenzonitrile and Example #4 Step J, Bwith DIEA, D with Na₂CO₃) [Table 2, Method 33, R_(t) = 12.1 min, or =negative]

AA.1.105 2.09 (b) 373 3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentanol (prepared using IIfrom benzoic acid and Example #4 Step J, B with DIEA, D with Na₂CO₃)[Table 2, Method 45, R_(t) = 9.1 min, or = negative]

AA.1.106 1.46 (b) 272 1-(2-ethyl-4-(3,3,3-trifluoropropoxy)cyclopentyl)-6H- pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (prepared using EE from Preparation #UU.1 with 3,3,3-trifluoropropanol, Z with NaOH, A from Example #1 Step D, HATU, and TEA,B with DIEA, D with NaOH) [Table 2, Method 46, R_(t) = 8.1 min]

AA.1.107 2.04 (b) 368 1-(2-ethyl-4-((tetrahydro-2H-pyran-4-yl)methoxy)cyclopentyl)-6H- pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (prepared using FFF from Example #22 Step D andtetrahydro-2H-pyran-4- carbaldehyde [Pharmacore], Z with NaOH, A fromExample #1 Step D, HATU, and TEA, B with DIEA, D with NaOH) [Table 2,Method 47, R_(t) = 10 min, or = negative]

AA.1.108 1.79 (b) 370 1-(2-ethyl-4-(2- methoxyethoxy)cyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazine (prepared using FFF fromExample #22 Step D and 2- methoxyacetaldehyde [BBB Scientific], Z withNaOH, A from Example #1 Step D, HATU, and TEA, B with DIEA, D with NaOH)[Table 2, Method 44, R_(t) = 11.7 min, or = negative]

AA.1.109 1.67 (b) 330 1-(2-ethyl-4-(2- methoxyethoxy)cyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazine pyrazine (prepared usingFFF from Example #22 Step D and 2-methoxyacetaldehyde [BBB Scientific],Z with NaOH, A from Example #1 Step D, HATU, and TEA, B with DIEA, Dwith NaOH) [Table 2, Method 44, R_(t) = 5.6 min, or = negative]

AA.1.110 1.70 (b) 330 N-((1R,4R)-3,3-dimethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfon- amide and N-((1S,4S)-3,3-dimethyl-4-(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfon- amide (prepared as in WO2009152133A1)[Table 2, Method 54, R_(t) = 12.4 min, or = negative]

AA.1.111 1.59 (b) 375 N-((1R,4R)-3,3-dimethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfon- amide and N-((1S,4S)-3,3-dimethyl-4-(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfon- amide (prepared as in WO2009152133A1)[Table 2, Method 54, R_(t) = 16.9 min, or = positive]

AA.1.112 1.59 (b) 375 2-(3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentyl)acetonitrile (preparedusing III from Preparation #25, Step E and diethylcyanomethylphosphonate; BBBB; W.1) [Table 2, Method 33, R_(t) = 9.6 min,or = negative]

AA.1.113 1.58 (b) 295 2-(3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentyl)acetonitrile (preparedusing III from Preparation #25, Step E and diethylcyanomethylphosphonate; BBBB; W.1) [Table 2, Method 33, R_(t) = 11.8min, or = negative]

AA.1.114 1.58 (a) 295 N-(3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentyl)cyclopropanesulfon-amide (prepared using D from Preparation #25 and NaOH, KK, P with NaBH₄,IIII, JJJJ with NaN₃, UUUU, K with cyclopropylsulfonyl chloride[Matrix], LL) [Table 2, Method 56, R_(t) = 12.2 min, or = negative]

AA.1.115 1.43 (a) 375 2-(3-(3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentylamino)oxetan-3-yl)acetonitrile (prepared using D from Preparation #25 and NaOH, KK, Pwith NaBH₄, IIII, JJJJ with NaN₃, UUUU, YYY with 2-(oxetan-3-ylidene)acetonitrile [prepared as described in J. Med. Chem, 2010,53(8) 3227-3246], LL) [Table 2, Method 5, R_(t) = 17.2 min, or =negative]

AA.1. 116 1.27 (a) 366 3-ethyl-1-methyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentanol (prepared using ZZZfrom Example #35, Step G and MeLi, LL) [Table 2, Method 33, R_(t) = 7.6min, or = negative]

AA.1.117 1.59 (a) 286 3-(3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyloxy)propanenitrile (prepared using YYY from Example #22,Step C, acrylonitrile and DBU, Z with NaOH, A with Example #1, Step D, Bwith SOCl₂ and TEA, and D with NaOH) [Table 2, Method 60, R_(t) = 10.9min, or = negative]

AA.1.118 1.70 (a) 325 3-(3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyloxy)propanenitrile (prepared using YYY from Example #22,Step C, acrylonitrile and DBU, Z with NaOH, A with Example #1, Step D, Bwith SOCl₂ and TEA, and D with NaOH) [Table 2, Method 60, R_(t) = 15.0min, or = negative]

AA.1.119 1.69 (a) 325 Ethyl 2-(3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentyl)acetate (preparedusing W from Preparation #AAAA.1 and PdOH₂ on C, and ZZZ with CH₃MgCl₂)[Table 2, Method 40, R_(t) = 6.0 min, or = negative]

AA.1.120 1.75 (a) 328 Ethyl 2-(3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentyl)acetate (preparedusing W from Preparation #AAAA.1 and PdOH₂ on C, and ZZZ with CH₃MgCl₂)[Table 2, Method 40, R_(t) = 10.3 min, or = negative]

AA.1.121 1.72 (a) 328 Ethyl 2-(3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentyl)acetate (preparedusing W from Preparation #AAAA.1 and PdOH₂ on C, and ZZZ with CH₃MgCl₂)[Table 2, Method 40, R_(t) = 14.8 min, or = negative]

AA.1.122 1.72 (a) 328 Ethyl 2-(3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentyl)acetate (preparedusing W from Preparation #AAAA.1 and PdOH₂ on C, and DDDD with (Z)-N′-hydroxycyclopropanecarboximid- amide [Tyger Scientific]) [Table 2,Method 61, R_(t) = 27.5 min, or = nd]

AA.1.123 1.95 (a) 378 Ethyl 2-(3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentyl)acetate (preparedusing W from Preparation #AAAA.1 and PdOH₂ on Carbon, and DDDD with(Z)-N′- hydroxycyclopropanecarboximid- amide [Tyger Scientific]) [Table2, Method 61, R_(t) = 29.4 min, or = nd]

AA.1.124 1.95 (a) 378 Ethyl 2-(3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentyl)acetate (preparedusing W from Preparation #AAAA.1 and PdOH₂ on C, and DDDD with (Z)-N′-hydroxycyclopropanecarboximid- amide [Tyger Scientific]) [Table 2,Method 61, R_(t) = 32.8 min, or = nd]

AA.1.125 1.95 (a) 378 (cis)-N-(1-cyanocyclopropyl)-3-ethyl-4-(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)pyrrolidine-1-carboxamide (prepared using J.1 from Example #36, stepF, CDI and 1- aminocyclopropanecarbonitrile · hydrochloride [Astatech],and D with Na₂CO₃) [Table 2, Method 62, R_(t) = 11.2 min, or = negative]

AA.1.126 1.47 (a) 365 (cis)-N-(1-cyanocyclopropyl)-3-ethyl-4-(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)pyrrolidine-1-carboxamide (prepared using J.1 from Example #36, stepF, CDI and 1- aminocyclopropanecarbonitrile · hydrochloride [Astatech],and D with Na₂CO₃) [Table 2, Method 62, R_(t) = 13.7 min, or = positive]

AA.1.127 1.45 (a) 365 (cis)-N-cyclobutyl-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)pyrrolidine-1-carboxamide (prepared using J.1 from Example #36, step F, CDI andcyclobutanamine, and D with NaOH) [Table 2, Method 34, R_(t) = 8.6 min,or = positive]

AA.1.128 1.58 (a) 354 (cis)-N-cyclobutyl-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)pyrrolidine-1-carboxamide (prepared using J.1 from Example #36, step F, CDI andcyclobutanamine, and D with NaOH) [Table 2, Method 34, R_(t) = 11.2 min,or = negative]

AA.1.129 1.60 (a) 354 (cis)-3-ethyl-N-(3-methylisothiazol-5-yl)-4-(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)pyrrolidine-1-carboxamide (prepared using J.1 from Example #36, StepF, CDI and 3- methylisothiazol-5-amine · hydrochloride, and D with NaOH)[Table 2, Method 63, R_(t) = 10.5 min, or = negative]

AA.1.130 1.56 (a) 397 (cis)-3-ethyl-N-(3-methylisothiazol-5-yl)-4-(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)pyrrolidine-1-carboxamide (prepared using J.1 from Example #36, StepF, CDI and 3- methylisothiazol-5-amine · hydrochloride, and D with NaOH)[Table 2, Method 63, R_(t) = 13.4 min, or = positive]

AA.1.131 1.56 (a) 397 (cis)-N-(cyanomethyl)-3-ethyl-4- (6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)pyrrolidine-1-carboxamide(prepared using J.1 from Example #36, Step F, CDI and 2-aminoacetonitrile, and D.2 with Na₂CO₃) [Table 2, Method 64, R_(t) =11.0 min, or = negative]

AA.1.132 1.42 (a) 339 (cis)-N-(cyanomethyl)-3-ethyl-4- (6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)pyrrolidine-1-carboxamide(prepared using J.1 from Example #36, Step F, CDI and 2-aminoacetonitrile, and D.2 with Na₂CO₃) [Table 2, Method 64, R_(t) =13.3 min, or = positive]

AA.1.133 1.42 (a) 339 (cis)-3-ethyl-N-(oxazol-4-ylmethyl)-4-(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)pyrrolidine-1-carboxamide (prepared using J.1 from Example #36, StepF, CDI and oxazol-4- ylmethanamine · hydrochloride [J & W Pharmlab], andD with NaOH) [Table 2, Method 65, R_(t) = 10.6 min, or = negative]

AA.1.134 1.44 (a) 381 (cis)-3-ethyl-N-(oxazol-4-ylmethyl)-4-(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)pyrrolidine-1-carboxamide (prepared using J.1 from Example #36, StepF, CDI and oxazol-4- ylmethanamine · hydrochloride hydrochloride [J & WPharmlab], and D with NaOH) [Table 2, Method 65, R_(t) = 11.8 min, or =positive]

AA.1.135 1.44 (a) 381 (cis)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1- carboxamide (prepared using J.1 fromExample #36, Step F, CDI and 2,2,2-trifluoroethanamine, and D with NaOH)[Table 2, Method 55, R_(t) = 14.5 min, or = negative]

AA.1.136 1.62 (a) 382 (cis)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1- carboxamide (prepared using J.1 fromExample #36, Step F, CDI and 2,2,2-trifluoroethanamine, and D with NaOH)[Table 2, Method 55, R_(t) = 17.3 min, or = positive]

AA.1.137 1.62 (a) 382 (3,3-difluoroazetidin-1-yl)((cis)-3-ethyl-4-(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)pyrrolidin-1-yl)methanone (prepared using D with Preparation #EEEE.1and NaOH) [Table 2, Method 64, R_(t) = 11.4 min, or = negative]

AA.1.138 1.65 (a) 376 (3,3-difluoroazetidin-1-yl)((cis)-3-ethyl-4-(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)pyrrolidin-1-yl)methanone (prepared using D with Preparation #EEEE.1and NaOH) [Table 2, Method 64, R_(t) = 12.9 min, or = positive]

AA.1.139 1.65 (a) 376 (cis)-3-ethyl-N-(oxetan-3-yl)-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)pyrrolidine-1-carboxamide (prepared using J.1 from Example #36, Step F, CDI andoxetan-3-amine [Synthonix], and D with NaOH) [Table 2, Method 65, R_(t)= 7.1 min, or = racemic]

AA.1.140 1.34 (a) 356 (cis)-3-ethyl-N-(oxetan-3-yl)-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)pyrrolidine-1-carboxamide (prepared using J.1 from Example #36, Step F, CDI andoxetan-3-amine [Synthonix], and D with NaOH) [Table 2, Method 65, R_(t)= 11.7 min, or = negative]

AA.1.141 1.43 (a) 356 (cis)-3-ethyl-N-(oxetan-3-yl)-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)pyrrolidine-1-carboxamide (prepared using J.1 from Example #36, Step F, CDI andoxetan-3-amine [Synthonix], and D with NaOH) [Table 2, Method 65, R_(t)= 13.3 min, or = positive]

AA.1.142 1.42 (a) 356 ((cis)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)pyrrolidin-1-yl)((R)-3-hydroxypyrrolidin-1-yl)methanone (prepared using EEEE from Example #36,Step F, with (R)- pyrrolidin-3-ol, and D with NaOH) [Table 2, Method 64,R_(t) = 10.1 min, or = negative]

AA 1.143 1.44 (a) 370 ((cis)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)pyrrolidin-1-yl)((R)-3-hydroxypyrrolidin-1-yl)methanone (prepared using EEEE from Example #36,Step F, (R)- pyrrolidin-3-ol, and D with NaOH) [Table 2, Method 64,R_(t) = 11.8 min, or = positive]

AA.1.144 1.42 (a) 370 ((cis)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)pyrrolidin-1-yl)((S)-3-hydroxypyrrolidin-1-yl)methanone (prepared using EEEE from Example #36,Step F, with (S)- pyrrolidin-3-ol, and D with NaOH) [Table 2, Method 67,R_(t) = 11.9 min, or = negative]

AA.1.145 1.40 (a) 370 ((cis)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)pyrrolidin-1-yl)((S)-3-hydroxypyrrolidin-1-yl)methanone (prepared using EEEE from Example #36,Step F, (S)-pyrrolidin- 3-ol, and D with NaOH) [Table 2, Method 67,R_(t) = 13.9 min, or = positive]

AA.1.146 1.42 (a) 370 (cis)-N-(cyclopropylmethyl)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo [4,3-a]pyrazin-1-yl)pyrrolidine-1-sulfonamide (prepared using ZZ from cyclopropylmethanamine and TEA, AAAwith Example #36, Step F, and D with NaOH). [Table 2, Method 33, R_(t) =10.0 min, or = positive]

AA.1.147 1.80 (a) 390 (cis)-N-(cyclopropylmethyl)-3-ethyl-4-(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)pyrrolidine-1-sulfonamide (prepared using ZZ fromcyclopropylmethanamine and TEA, AAA with Example #36, Step F, and D withNaOH). [Table 2, Method 33, R_(t) = 14.0 min, or = negative]

AA.1.148 1.78 (a) 390 (cis)-N-(2-cyclopropylethyl)-3-ethyl-4-(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)pyrrolidine-1-carboxamide (prepared using J.1 from Example #36, StepF, CDI and 2- cyclopropylethanamine [Oakwood], and D with NaOH). [Table2, Method 33, R_(t) = 6.8 min, or = positive]

AA.1.149 1.69 (a) 368 (cis)-N-(2-cyclopropylethyl)-3-ethyl-4-(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)pyrrolidine-1-carboxamide (prepared using J.1 from Example #36, StepF, CDI and 2- cyclopropylethanamine [Oakwood], and D with NaOH). [Table2, Method 33, R_(t) = 9.3 min, or = negative]

AA.1.150 1.70 (a) 368 (cis)-3-ethyl-N-(oxetan-3-yl)-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)pyrrolidine-1-sulfonamide (prepared using ZZ from oxetan-3-amine [Synthonix] and TEA,AAA with Example #36, Step F, and D with NaOH). [Table 2, Method 11 ,R_(t) = 6.6 min, or = positive]

AA.1.151 1.58 (a) 392 (cis)-3-ethyl-N-(oxetan-3-yl)-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)pyrrolidine-1-sulfonamide (prepared using ZZ from oxetan-3-amine [Synthonix] and TEA,AAA with Example #36, Step F, and D with NaOH). [Table 2, Method 11,R_(t) = 10.8 min, or = negative]

AA.1.152 1.58 (a) 392 (cis)-N-cyclobutyl-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)pyrrolidine-1-sulfonamide (prepared using ZZ from cyclobutanamine and TEA, AAA withExample #36, Step F, and D with NaOH). [Table 2, Method 33, R_(t) = 9.5min, or = positive]

AA.1.153 1.79 (a) 390 (cis)-N-cyclobutyl-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)pyrrolidine-1-sulfonamide (prepared using ZZ from cyclobutanamine and TEA, AAA withExample #36, Step F, and D with NaOH). [Table 2, Method 33, R_(t) = 12.7min, or = negative]

AA.1.154 1.79 (a) 390 (cis)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)pyrrolidine-1- sulfonamide(prepared using ZZ from 2-aminoacetonitrile and TEA, AAA with Example#36, Step F, and D with NaOH). [Table 2, Method 68, R_(t) = 4.9 min, or= positive]

AA.1.155 1.48 (a) 336 (cis)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)pyrrolidine-1- sulfonamide(prepared using ZZ from 2-aminoacetonitrile and TEA, AAA with Example#36, Step F, and D with NaOH). [Table 2, Method 68, R_(t) = 10.4 min, or= negative]

AA.1.156 1.48 (a) 336 (cis)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1- sulfonamide (prepared using ZZ from2,2,2-trifluoroethanamine and TEA, AAA with Example #36, Step F, and Dwith NaOH). [Table 2, Method 66, R_(t) = 12.9 min, or = negative]

AA.1.157 1.85 (a) 418 (cis)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1- sulfonamide (prepared using ZZ from2,2,2-trifluoroethanamine and TEA, AAA with Example #36, Step F, and Dwith NaOH). [Table 2, Method 66, R_(t) = 15.8 min, or = positive]

AA.1.158 1.85 (a) 418 (cis)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N- (2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (prepared using J.1 with Preparation #F.1.1 and 2,2,2-trifluoroethanamine, and D with NaOH). [Table 2, Method 69, R_(t) = 11.2min, or = positive]

AA.1.159 1.52 (a) 381 (cis)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N- (2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (prepared using J.1 with Preparation #F.1.1 and 2,2,2-trifluoroethanamine, and D with NaOH). [Table 2, Method 69, R_(t) = 15.5min, or = negative]

AA.1.160 1.52 (a) 381 1-((1,2,4)-4-(4,4- difluorocyclohexyloxy)-2-ethylcyclopentyl)-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazine(prepared using II from Example #22 Step C with 4-nitrobenzoic acid, SSwith NaOH, VV, FFF with 4,4- difluorocyclohexanone [Small Molecule], Zwith NaOH, A with Example #1 Step D, HATU and TEA, B with DIEA, D withNaOH) [Table 2, Method 28, R_(t) = 10.1 min, or = negative]

AA.1.161 2.07 (b) 390 1-((1,2,4)-4-(4,4- difluorocyclohexyloxy)-2-ethylcyclopentyl)-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazine(prepared using II from Example #22 Step C with 4-nitrobenzoic acid, SSwith NaOH, VV, FFF with 4,4- difluorocyclohexanone [Small Molecule], Zwith NaOH, A with Example #1 Step D, HATU and TEA, B with DIEA, D withNaOH) [Table 2, Method 28, R_(t) = 15.1 min, or = negative]

AA.1.162 2.05 (b) 390 1-((1,2,4)-2-ethyl-4-((1,4)-4-(trifluoromethyl)cyclohexyloxy)cyclo- pentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (prepared using II from Example #22Step C with 4-nitrobenzoic acid, SS with NaOH, VV, FFF with 4-trifluoromethylcyclohexanone [Matrix], Z with NaOH, A with Example #1Step D, HATU and TEA, B with DIEA, D with NaOH) [Table 2, Method 58,R_(t) = 7.8 min, or = negative]

AA.1.163 2.34 (b) 422 1-((1,2,4)-2-ethyl-4-((1,4)-4-(trifluoromethyl)cyclohexyloxy)cyclo- pentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (prepared using II from Example #22Step C with 4-nitrobenzoic acid, SS with NaOH, VV, FFF with 4-trifluoromethylcyclohexanone [Matrix], Z with NaOH, A with Example #1Step D, HATU and TEA, B with DIEA, D with NaOH) [Table 2, Method 51,R_(t) = 14.6 min, or = negative]

AA.1.164 2.22 (b) 422 1-((1,2,4)-4-(1,4)-4-(trifluoromethyl)cyclohexyloxy)cyclo- pentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (prepared using II from Example #22Step C with 4-nitrobenzoic acid, SS with NaOH, VV, FFF with 4-trifluoromethylcyclohexanone [Matrix], Z with NaOH, A with Example #1Step D, HATU and TEA, B with DIEA, D with NaOH) [Table 2, Method 58,R_(t) = 14.6 min, or = negative]

AA.1.165 2.29 (b) 422 1-((1,2,4)-4-(1,4)-4-(trifluoromethyl)cyclohexyloxy)cyclo- pentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (prepared using II from Example #22Step C with 4-nitrobenzoic acid, SS with NaOH, VV, FFF with 4-trifluoromethylcyclohexanone [Matrix], Z with NaOH, A with Example #1Step D, HATU and TEA, B with DIEA, D with NaOH) [Table 2, Method 51,R_(t) = 15.8 min, or = negative]

AA.1.166 2.22 (b) 422 (1,4)-4-((1,3,4)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyloxy)cyclohexanecarbo- nitrile (prepared using II fromExample #22 Step C with 4- nitrobenzoic acid, SS with NaOH, VV, FFF with4- oxocyclohexanecarbonitrile [Beta Pharma], Z with NaOH, A with Example#1 Step D, HATU and TEA, B with DIEA, D with NaOH) [Table 2, Method 57,R_(t) = 14.3 min, or = negative]

AA.1.167 1.80 (b) 379 (1,4)-4-((1,3,4)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyloxy)cyclohexanecarbo- nitrile (prepared using II fromExample #22 Step C with 4- nitrobenzoic acid, SS with NaOH, VV, FFF with4- oxocyclohexanecarbonitrile [Beta Pharma], Z with NaOH, A with Example#1 Step D, HATU and TEA, B with DIEA, D with NaOH) [Table 2, Method 57,R_(t) = 19.5 min, or = negative]

AA.1.168 1.80 (b) 379 (cis-3-(3H-imidazo[1,2- a]pyrrolo[2,3-e]pyrazin-8-yl)cyclobutyl)methanamine (prepared from Preparation #36 using N, R withtrimethylsilyl diazomethane, S with Example #3 Step E, E with TFA, KKKKwith 2,2,3,3,3-pentafluoropropanoic anhydride, D with NaOH, F.1 with HBrin AcOH) [Table 2, Method 71, R_(t) = 29.8 min]

AA.1.169 2.10 (r) 242 (trans-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8- yl)cyclobutyl)methanamine (prepared fromPreparation #36 using N, R with trimethylsilyl diazomethane, S withExample #3 Step E, E with TFA, KKKK with 2,2,3,3,3-pentafluoropropanoicanhydride, D with NaOH, F.1 with HBr in AcOH) [Table 2, Method 71, R_(t)= 27.9 min]

AA.1.170 2.10 (r) 242 N-((5-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4- methyltetrahydrofuran-2-yl)methyl)-3,3,3- trifluoropropane-1-sulfonamide (prepared using E withHCl from Preparation #43, K with 3,3,3-trifluoropropane-1- sulfonylchloride (Matrix), Z with NaOH, H with N,O- dimethylhydroxylamine,hydrochloric acid, MMMM with methylmagnesium bromide, M.1, LLLL, S fromExample #3 Step E, E with TFA, KKKK with TFA & TFAA, D with Na₂CO₃)[Table 2, Method 51, R_(t) = 46.2 min, or = positive]

AA.171 1.72 (a) 432 N-((5-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4- methyltetrahydrofuran-2-yl)methyl)-3,3,3-trifluoropropane- 1-sulfonamide (prepared using E withHCl from Preparation #43, K with 3,3,3-trifluoropropane-1- sulfonylchloride (Matrix), Z with NaOH, H with N,O- dimethylhydroxylamine,Hydrochloric Acid, MMMM with methylmagnesium bromide, M.1, LLLL, S fromExample #3 Step E, E with TFA, KKKK with TFA & TFAA, D with Na₂CO₃)[Table 2, Method 51, R_(t) = 41.2 min, or = negative]

AA.172 1.72 (a) 432 3-ethyl-1- (morpholinosulfonylmethyl)-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo [4,3-a]pyrazin-1-yl)cyclopentanol(prepared using NNNN with Preparation #41 and Example 35 Step G, LL)[Table 2, Method 52, R_(t) = 12 min, or = negative]

AA.173 1.63 (a) 435 3-ethyl-1- (morpholinosulfonylmethyl)-4-(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin- 1-yl)cyclopentanol(prepared using NNNN with Preparation #41 and Example 35 Step G, LL)[Table 2, Method 52, R_(t) = 8.9 min, or = negative]

AA.174 1.60 (a) 435 3-ethyl-1- (morpholinosulfonylmethyl)-4-(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin- 1-yl)cyclopentanol(prepared using NNNN with Preparation #41 and Example 35 Step G, LL)[Table 2, Method 53, R_(t) = 18.7 min, or = negative]

AA.175 1.56 (a) 435 8-(2-methyl-4-(tetrahydro-2H-pyran-4-yloxy)cyclopentyl)-3H- imidazo[1,2-a]pyrrolo[2,3- e]pyrazine(prepared using P from Example #24 Step H, VV, FFF withdihydro-2H-pyran- 4(3H)-1-one, Z with NaOH, R, S from Example #3 Step E,E with TFA, KKKK with PFPAA, D with NaOH) [Table 2, Method 21, R_(t) =17.6 min, or = negative]

AA.176 1. 60 (a) 341 8-(2-methyl-4-(tetrahydro-2H-pyran-4-yloxy)cyclopentyl)-3H- imidazo[1,2-a]pyrrolo[2,3- e]pyrazine(prepared using P from Example #24 Step H, VV, FFF withdihydro-2H-pyran- 4(3H)-one, Z with NaOH, R, S from Example #3 Step E, Ewith TFA, KKKK with PFPAA, D with NaOH) [Table 2, Method 21, R_(t) = 5.1min, or = negative]

AA.177 1.65 (a) 341 8-(2-methyl-4-(tetrahydro-2H-pyran-4-yloxy)cyclopentyl)-3H- imidazo[1,2-a]pyrrolo[2,3- e]pyrazine(prepared using P from Example #24 Step H, II with 4-nitrobenzoic acid,SS, VV, FFF with dihydro-2H- pyran-4(3H)-one, Z with NaOH, R, S fromExample #3 Step E, E with TFA, KKKK with PFPAA, D with NaOH) [Table 2,Method 28, R_(t) = 18.6 min, or = negative]

AA.178 1.85 (a) 341 N-(3-methyl-4-(7-methyl-3H-imidazo[1,2-a]pyrrolo[2,3- e]pyrazin-8-yl)cyclopentyl)cyclopropanesulfon- amide (prepared using LLLL fromPreparation #M.1.1, S from Example #3 Step E, E with TFA, T withLawesson's Reagent, D with NaOH) [Table 2, Method 6, R_(t) = 14.2 min,or = negative]

AA.179 1.66 (a) 374 N-(3-methyl-4-(7-methyl-3H-imidazo[1,2-a]pyrrolo[2,3- e]pyrazin-8-yl)cyclopentyl)cyclopropanesulfon- amide (prepared using LLLL fromPreparation #M.1.1, S from Example #3 Step E, E with TFA, T withLawesson's Reagent, D with NaOH) [Table 2, Method 6, R_(t) = 9.3 min, or= positive

AA.180 1.66 (a) 374 N,N-dibenzyl-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8- yl)cyclopentanamine (prepared using X from 3-oxocyclopentanecarboxylic acid and dibenzylamine, FFFFF, GGGGG withPreparation #E.1.1, KKKK with PFPAA, D with NaOH, Y with Pd(OH)₂) [Table2, Method 59, R_(t) = 10.5 min, or = ND]

AA.1.181 1.18 (b) 242 N,N-dibenzyl-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8- yl)cyclopentanamine (prepared using X from 3-oxocyclopentanecarboxylic acid and dibenzylamine, FFFFF, GGGGG withPreparation #E.1.1,, KKKK with PFPAA, D with NaOH, Y with Pd(OH)₂)[Table 2, Method 59, R_(t) = 12.0 min, or = ND]

AA.1.182 1.17 (b) 242 N,N-dibenzyl-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8- yl)cyclopentanamine (prepared using X from 3-oxocyclopentanecarboxylic acid and dibenzylamine, FFFFF, GGGGG withPreparation #E.1.1, KKKK with PFPAA, D with NaOH, Y with Pd(OH)₂) [Table2, Method 59, R_(t) = 13.5 min, or = ND]

AA.1.183 1.11 (b) 242 N,N-dibenzyl-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8- yl)cyclopentanamine (prepared using X from 3-oxocyclopentanecarboxylic acid and dibenzylamine, FFFFF, GGGGG withPreparation #E.1.1, KKKK with PFPAA, D with NaOH, Y with Pd(OH)₂) [Table2, Method 59, R_(t) = 17.1 min, or = ND]

AA.1.184 1.17 (b) 242 N-(2-cyclopropylethyl)-N-((1S,3R,4S)-3-ethyl-4-(6H- pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)oxetan- 3-amine (prepared using X fromPreparation #25 and oxetan-3-amine [Synthonix], X using 2-cyclopropylacetaldehyde [Anichem], and D with NaOH [Table 2, Method 55,R_(t) = 22.7 min, or = negative]

AA.1.185* 1.38 (a) 395 N-(cyclopropylmethyl)-N-((1S,3R,4S)-3-ethyl-4-(6H- pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)oxetan- 3-amine (prepared using X fromPreparation #25 and oxetan-3-amine [Synthonix], X usingcyclopropanecarbaldehyde, and D with NaOH [Table 2, Method 6, R_(t) =15.9 min, or = negative]

AA.1.186* 1.21 (a) 381

General Procedure BB: Acidic Hydrolysis of an Acetyl Protected Amine

To a solution of an N-acetamide (preferably 1 equiv) in an organicsolvent (such as 1,4-dioxane) is added an acid, such as 6 N aqueous HCl(3-100 equiv, preferably 30-40 equiv). The reaction mixture is heated atabout 60-100° C. (preferably about 90-100° C.) for about 1-24 h(preferably about 16 h). The reaction mixture is allowed to cool toambient temperature before it is partitioned between an organic solvent(such as EtOAc or DCM) and aqueous base (such as NaHCO₃, Na₂CO₃ or NaOH,preferably NaHCO₃) and the aqueous layer is optionally extracted withadditional organic solvent (such as EtOAc or DCM). The organic layer isdried over anhydrous MgSO₄ or Na₂SO₄, filtered, and concd under reducedpressure.

Illustration of General Procedure BB Preparation #BB.1*(1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine

To a solution ofN-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)acetamide(6.0 g, 12.86 mmol, Example #8, Step L) in 1,4-dioxane (78 mL) was addedaqueous HCl (6 N, 75 mL, 450 mmol). The reaction mixture was heated atabout 95° C. for about 16 h. The reaction was cooled to ambienttemperature and the solvent was removed under reduced pressure. Theresidue was diluted with DCM (50 mL) and washed with saturated aqueousNaHCO₃ (100 mL). The aqueous portion was extracted with additional DCM(3×50 mL) and the combined organic layers were dried over anhydrousMgSO₄, filtered, and concd under reduced pressure. The crude materialwas purified by silica gel chromatography eluting with a gradient of0-100% DCM/MeOH/NH₄OH (950:45:5) in DCM to give(1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine(3.05 g, 56%) as a tan solid: LC/MS (Table 1, Method a) R_(t)=1.85 min;MS m/z: 425 (M+H)⁺.

General Procedure CC: Formation of a Sulfamoyl Chloride

A round bottom flask is charged with an amine or amine salt (preferably1 equiv) in an organic solvent (for example, DCM or toluene ortoluene/DCM). If an amine salt is used, a base such as TEA or DIEA,preferably DIEA (1-10 equiv, preferably 2.5 equiv) is added and thereaction is stirred for about 1-20 min, (preferably about 5 min). Thereaction mixture is then cooled to about 50-20° C., (preferably about30° C.) for about 1-10 min (preferably about 5 min). Sulfuryl chlorideor a solution of sulfuryl chloride (such as 1 M in DCM), preferablysulfuryl chloride (1-10 equiv, preferably 3.5 equiv) is added dropwiseto the reaction mixture. The reaction mixture is stirred at about 50-0°C. (preferably about 30° C.) for about 0.5-4 h (preferably about 1 h)then is allowed to warm to ambient temperature and is stirred for about1-24 h (preferably about 5 h). The reaction is then diluted with anorganic solvent (such as DCM, EtOAc or toluene), and is washed with anaqueous solution of HCl (such as 0.1-6 M, preferably 1 M). Optionally,the reaction is poured over crushed ice and the layers are separated.The organic extracts are optionally washed with water and/or brine,dried over anhydrous Na₂SO₄ or MgSO₄, filtered or decanted, and concdunder reduced pressure.

Illustration of General Procedure CC Preparation #CC.1azetidine-1-sulfonyl chloride

An oven dried flask is charged with azetidine hydrochloride (2.00 g,21.38 mmol), DIEA (5.60 mL, 32.10 mmol), and DCM (50 mL). The reactionmixture was stirred for about 5 min at ambient temperature and thencooled to about −30° C. in a dry ice/MeCN bath for about 5 min. Sulfurylchloride (4.30 mL, 53.60 mmol, Acros) was added dropwise over about 5min. The reaction mixture was stirred at about −30° C. for about 1 h,then at ambient temperature for about 5 h. The reaction mixture wasdiluted with aqueous HCl (1 N, 15 mL). The layers were separated and theaqueous layer was extracted with DCM (10 mL). The combined organiclayers were washed with aqueous HCl (1 N, 10 mL) and brine (20 mL). Theorganic layers were dried over anhydrous MgSO₄, filtered, and thesolvent was removed under reduced pressure to give azetidine-1-sulfonylchloride (1.86 g, 56%): ¹H NMR (CDCl₃) δ 4.25-4.01 (m, 4H), 2.51-2.29(m, 2H).

General Procedure DD: Formation of a Sulfonylurea

To a solution of an amine (preferably 1 equiv) and a base such as TEA,DIEA, Na₂CO₃, or K₂CO₃ (1-20 equiv, preferably 2.5 equiv of TEA) in anorganic solvent (such as DMF, DMA, DCM, THF, or 1,4-dioxane, preferablyDMF) at about −10° C. to ambient temperature (preferably about 0° C.) isadded a sulfamoyl chloride (1-5 equiv, preferably 2.2 equiv). Thereaction mixture is stirred for about 1-48 h (preferably about 2-4 h) atambient temperature. In cases where the reaction does not proceed tocompletion as monitored by TLC, LC/MS, or HPLC, additional sulfamoylchloride is added portionwise (1-20 equiv in total, preferably 3 equivper addition) to the reaction mixture about every 12-72 h (preferablyabout every 24 h) and the reaction mixture is stirred at ambienttemperature until progress of the reaction has halted as monitored byTLC, LC/MS, or HPLC. The reaction mixture is concd to dryness underreduced pressure and/or diluted with an organic solvent (such as EtOAcor DCM) and water. The combined organic extracts are optionally washedwith water and/or brine, dried over anhydrous Na₂SO₄ or MgSO₄, filtered,or decanted, and concd under reduced pressure. Optionally, the reactionis diluted with water and the solid is collected by vacuum filtration,washed with additional water, and dried under vacuum.

Illustration of General Procedure DD Preparation #DD.1*N-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)azetidine-1-sulfonamide

A flask was charged with(1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine(0.200 g, 0.471 mmol, Example #8, Step M) and DMF (4 mL). The solutionwas cooled to about 0° C. followed by the addition of TEA (0.16 mL, 1.2mmol) and azetidine-1-sulfonyl chloride (0.165 g, 1.06 mmol, Preparation#CC.1). The reaction mixture was warmed to ambient temperature and wasstirred for about 2 h. The solvent was removed under reduced pressureand DCM (10 mL) was added to the resulting residue. The organic solutionwas washed with water and brine (5 mL each). The combined organics weredried over anhydrous MgSO₄, filtered, and concd under reduced pressureto give a brown oil. The crude material was purified by silica gelchromatography eluting with a gradient of 0-70% EtOAc in DCM to affordN-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl)azetidine-1-sulfonamide(0.20 g, 77%) as a white solid: LC/MS (Table 1, Method a) R_(t)=2.39min; MS m/z: 544 (M+H)⁺.

TABLE DD.1 Example prepared from1-((3R,4R)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine hydrochloride (Example #5, Step J) usingGeneral Procedure DD R_(t) min (Table 1, m/z ESI + Sulfonyl chlorideProduct Example # Method) (M + H)⁺ pyrrolidine-1-sulfonyl chloride[ChemBridge-BB]

DD.1.1* 1.79 (b) 389

TABLE DD.2 Example prepared from(R)-1-(piperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3- e]pyrazinehydrochloride (Example #6, Step H) using General Procedure DD R_(t) min(Table 1, m/z ESI + Sulfonyl chloride Product Example # Method) (M + H)⁺pyrrolidine-1-sulfonyl chloride [ChemBridge-BB]

DD.2.1* 1.67 (b) 375General Procedure EE: Ether Formation from a TrichloroacetimidateDerivative

To an alcohol (preferably 1 equiv) in a mixture of organic solvents suchas DCM and cyclohexane (1:1 to 1:5, preferably 1:2) at about −10-5° C.(preferably about 0° C.) is added a 2,2,2-trichloroacetimidatederivative (1-3 equiv, preferably 1.6 equiv) followed by a slow additionof an acid such as p-toluenesulfonic acid or trifluoromethanesulfonicacid (0.05-1 equiv, preferably 0.08-0.1 equiv). The reaction mixture isstirred at about −10-5° C. (preferably about 0° C.) for about 5-60 min(preferably about 30 min). The ice bath is removed and the reactionmixture is stirred at ambient temperature for about 2-24 h (preferablyabout 16 h). The suspension is poured into ice water and stirred forabout 5-60 min (preferably about 30 min). The suspension is eitherfiltered while washing with an organic solvent such as DCM or dilutedwith an organic solvent such as DCM. The layers are separated and theaqueous layer is extracted with an organic solvent such as DCM. Thecombined organic layers are washed with water, dried over anhydrousNa₂SO₄ or MgSO₄, filtered and concd under reduced pressure.

Illustration of General Procedure EE Preparation #EE.1 Ethyl2-ethyl-4-(4-methoxybenzyloxy)cyclopentanecarboxylate

To a mixture of ethyl 2-ethyl-4-hydroxycyclopentanecarboxylate (37.78 g,203 mmol, Preparation #P.1) in DCM (100 mL) and cyclohexane (200 mL) atabout 0° C. was added 4-methoxybenzyl 2,2,2-trichloroacetimidate (93.58g, 331 mmol) followed by dropwise addition of trifluoromethanesulfonicacid (1.6 mL, 18.0 mmol) over about 35 min. The reaction mixture wasstirred at about 0° C. for about 30 min. The ice bath was removed andthe reaction mixture was stirred at ambient temperature for about 16 h.The suspension was poured into ice-water (500 mL) and stirred for about30 min. The solid was removed by filtration while washing with DCM (100mL). The layers in the filtrate were separated and the aqueous layer wasextracted with DCM (3×200 mL). The combined organic layers were washedwith water (200 mL), dried over anhydrous MgSO₄, filtered, and concdunder reduced pressure. The crude material was purified using silica gelchromatography eluting with a gradient of 0-100% DCM:EtOAc (95:5) in DCMto give ethyl 2-ethyl-4-(4-methoxybenzyloxy)cyclopentanecarboxylate(39.80 g, 64%): LC/MS (Table 1, Method b) R_(t)=2.90 min; MS m/z: 307(M+H)⁺.

General Procedure FF: Deprotection of a PMB Protected Alcohol

To a PMB protected alcohol (preferably 1 equiv) in an mixture ofsolvents such as DCM and water (1:1 to 7:1, preferably 5:1) is added2,3-dichloro-5,6-dicyano-p-benzoquinone (1-2 equiv, preferably 1.2equiv). The reaction mixture is stirred at ambient temperature for about8-24 h (preferably about 16 h). The solid is removed by filtration whilewashing with an organic solvent such as DCM. The layers in the filtrateare separated and the organic layer is washed with saturated aqueousNaHCO₃ and brine, dried over anhydrous Na₂SO₄ or MgSO₄, filtered, andconcd under reduced pressure.

Illustration of General Procedure FF Preparation #FF.13-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanol

To2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine(1.153 g, 2.11 mmol, prepared using Z from Preparation #EE.1, A fromExample #1, Step D, HATU, and TEA, B with DIEA) in DCM (18 mL) and water(3.5 mL) was added 2,3-dichloro-5,6-dicyano-p-benzoquinone (0.576 g,2.54 mmol). The reaction mixture was stirred at ambient temperature forabout 16 h. The solid was removed by filtration while washing with DCM(150 mL). The organic layer was separated and washed with saturatedaqueous NaHCO₃ (2×40 mL) and brine (40 mL), dried over anhydrous MgSO₄,filtered, and concd under reduced pressure. The residue was purifiedusing silica gel chromatography (40 g) eluting with a gradient of30-100% EtOAc in DCM to give3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanol(0.672 g, 75%): LC/MS (Table 1, Method b) R_(t)=2.09 min; MS m/z: 426(M+H)⁺.

General Procedure GG: Formation of a Lactone

To a γ-alcohol carboxylic acid (preferably 1 equiv) in an organicsolvent such as DCM is added a base (such as TEA, 3-5 equiv, preferably3 equiv) and BOP-Cl (1-2 equiv, preferably 1.2 equiv). The reactionmixture is stirred at ambient temperature for about 1-5 h (preferablyabout 2 h). The reaction mixture is poured into an organic solvent(preferably Et₂O). The solid is removed by filtration while washing withan organic solvent such as Et₂O. The filtrate is concd under reducedpressure. Alternatively, the filtrate is washed with saturated aqueousNaHCO₃, 1 N aqueous citric acid, and brine, dried over anhydrous Na₂SO₄or MgSO₄, filtered, and concd under reduced pressure.

Illustration of General Procedure GG Preparation #GG.1*(1S,4S,5R)-5-ethyl-2-oxabicyclo[2.2.1]heptan-3-one

To (1S,2R,4S)-2-ethyl-4-hydroxycyclopentanecarboxylic acid (0.943 g,5.96 mmol, Example #4, Step H) in DCM (60 mL) was added TEA (2.5 mL, 18mmol) and BOP-Cl (1.82 g, 7.15 mmol). The reaction mixture was stirredat ambient temperature for about 2 h then poured into Et₂O (350 mL). Thesolid was removed by filtration while washing with Et₂O (50 mL). Thefiltrate was concd under reduced pressure to give a yellow oil which wasdissolved in DCM (5 mL) and Et₂O was added to give a solid. Thesupernatant was decanted and the solid was washed with additional Et₂O.The combined organic extracts were concd under reduced pressure to give(1S,4S,5R)-5-ethyl-2-oxabicyclo[2.2.1]heptan-3-one containing about 15mol % TEA (0.912 g, 99% crude): ¹H NMR (CDCl₃) δ 4.85 (s, 1H), 2.88 (s,1H), 2.19 (m, 2H), 2.08 (m, 1H), 1.69 (m, 1H), 1.41 (m, 3H), 0.97 (t,J=5.4, 3H).

General Procedure HH: Opening of a Lactone with an Amine or Hydrazine

To a lactone (preferably 1 equiv) in an organic solvent such as1,4-dioxane or DCM (preferably 1,4-dioxane) is added a hydrazine (1-1.5equiv, preferably 1 equiv). Alternatively, a lactone (preferably 1equiv) is added to a solution of an HCl salt of an amine and DIEA (1-1.5equiv, preferably 1 equiv) in an organic solvent or mixture of solvents(such as 1,4-dioxane, DCM, or DCM/DMF, preferably DCM). The reactionmixture is stirred at ambient temperature or heated at about 40-100° C.(preferably about 80° C. when 1,4-dioxane is used, reflux when DCM isused) for about 1-24 h (preferably about 16 h). If heating, the reactionmixture is cooled to ambient temperature. In cases where the reactiondoes not proceed to completion as monitored by TLC, LC/MS or HPLC,trimethylaluminum (1-8 equiv, preferably 3 equiv) is added dropwise neator in solution (such as 2 M in chlorobenzene, 2 M in heptane, or 2 M intoluene, preferably 2M in toluene) after the optional addition of anorganic solvent (such as 1,4-dioxane, DCM, or DMF, preferably1,4-dioxane) and the reaction mixture is stirred at ambient temperaturefor about 0.25-16 h (preferably about 0.5 h). Optionally,trimethylaluminum neat or in solution as described above may be addedfrom the onset of the reaction. Aqueous HCl (1 N, 3-10 equiv, preferably8 equiv) is added dropwise and the reaction mixture is stirred for about10-60 min (preferably about 30 min). The layers are separated and theaqueous layer is extracted with an organic solvent such as EtOAc or DCM(preferably EtOAc). The combined organic portions are washed with water,saturated aqueous NaHCO₃, brine and dried over anhydrous Na₂SO₄ orMgSO₄, filtered, and concd under reduced pressure.

Illustration of General Procedure HH Preparation #HH.1*(1S,2R,4S)-2-ethyl-4-hydroxy-N′-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)cyclopentanecarbohydrazide

To (1S,4S,5R)-5-ethyl-2-oxabicyclo[2.2.1]heptan-3-one (0.835 g, 5.96mmol, Preparation #GG.1) in 1,4-dioxane (12 mL) was added2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (Example #1, Step D, 1.81g, 5.96 mmol). The reaction mixture was heated at about 80° C. for about16 h then cooled to ambient temperature. 1,4-Dioxane (25 mL) andtrimethylaluminum (2 N in toluene, 9 mL, 18 mmol) were addedsequentially. The reaction mixture was stirred at ambient temperaturefor about 30 min. Aqueous HCl (1 N, 50 mL) was added dropwise and thereaction mixture was stirred for about 30 min. The layers wereseparated. The aqueous portion was extracted with EtOAc (2×100 mL). Thecombined organic extracts were washed with water (10 mL), saturatedaqueous NaHCO₃ (15 mL), brine (15 mL) and dried over anhydrous MgSO₄,filtered, and concd under reduced pressure. The residue was purifiedusing silica gel chromatography (40 g) eluting with 100% EtOAc to give(1S,2R,4S)-2-ethyl-4-hydroxy-N′-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)cyclopentane-carbohydrazide(1.887 g, 53%): LC/MS (Table 1, Method b) R_(t)=2.05 min; MS m/z: 444(M+H)⁺.

TABLE HH.1 Examples prepared from1-((3R,4R)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine hydrochloride (Example #5, Step J) usingGeneral Procedure HH with DIEA R_(t) min (Table 1, m/z ESI + LactoneProduct Example # Method) (M + H)⁺ β-propiolactone

HH.1.1* 1.02 (b) 328

General Procedure II: Mitsunobu Reaction of an Alcohol

To an alcohol (preferably 1 equiv) in an organic solvent such as THF,benzene, toluene, or 1,4-dioxane (preferably THF) is added a suitablyacidic reactant (such as a carboxylic acid, a phenol or a heteroarylalcohol, 1-3 equiv, preferably 1.5 equiv), followed bytri-n-butylphosphine, triphenylphosphine or polymer boundtriphenylphosphine (preferably polymer bound triphenylphosphine, 1-3equiv, preferably 1.5 equiv), and TEA (1-6 equiv, preferably 4.5 equiv).TMAD, 1,1′-(azodicarbonyl)dipiperidine, DIAD or DEAD (preferably DEAD,1-3 equiv, preferably 1.5 equiv) is added dropwise. The reaction mixtureis stirred at ambient temperature for about 5-48 h (preferably about 16h). Alternatively, after about 0.1-24 h (preferably about 1 h),additional phosphine reagent (0.2-2 equiv, preferably 0.75 equiv) andTMAD, 1,1′-(azodicarbonyl)dipiperidine, DIAD or DEAD (0.2-1 equiv,preferably 0.75 equiv) are added to drive the reaction to completion.When polymer bound reagent is used, the reaction mixture is filtered andwashed with a mixture of solvents such as DCM, EtOAc and MeOH(preferably DCM then MeOH). The filtrate is concd under reducedpressure. When no polymer bound reagent is used, the reaction mixture isdiluted with an organic solvent such as DCM or EtOAc and then washedwith water, saturated aqueous NaHCO₃, brine and dried over anhydrousNa₂SO₄ or MgSO₄, filtered, and concd under reduced pressure.

Illustration of General Procedure II Preparation #II.1*(1S,2R,4R)-4-(4-cyanophenoxy)-2-ethyl-N′-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)cyclopentanecarbohydrazide

To(1S,2R,4S)-2-ethyl-4-hydroxy-N-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)cyclopentane-carbo-hydrazide(0.885 g, 1.99 mmol, Example #4, Step J) in THF (15 mL) was added4-hydroxybenzonitrile (0.357 g, 2.99 mmol), triphenylphosphine (0.998 g,2.99 mmol, polymer bound, 3 mmol/g), and TEA (1.3 mL, 9 mmol). DEAD(0.47 mL, 2.99 mmol) was added dropwise. The reaction mixture wasstirred for about 1 h then additional triphenylphosphine (0.50 g, 1.50mmol, polymer bound, 3 mmol/g) and DEAD (0.2 mL, 1.3 mmol) were addedand the reaction mixture was stirred at ambient temperature for about 16h. The solid was removed by filtration while washing with DCM (5×5 mL)then MeOH (4×5 mL). The filtrate was concd under reduced pressure andthe residue was purified using silica gel chromatography (40 g) elutingwith a gradient of 0-40% EtOAc in DCM to give(1S,2R,4R)-4-(4-cyanophenoxy)-2-ethyl-N′-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)cyclopentanecarbohydrazide(0.958 g, 88%) as a yellow foam: LC/MS (Table 1, Method b) R_(t)=2.56min; MS m/z: 545 (M+H)⁺.

General Procedure JJ: Displacement of a Halide with an Alcohol

To an alcohol (preferably 1 equiv) in an organic solvent such as DMF,THF or 1,4-dioxane (preferably DMF) at about 0-25° C. (preferablyambient temperature) is added NaH (60% dispersion in mineral oil, 1-4equiv, preferably 1.2 equiv) in portions. After about 2-60 min(preferably about 5 min), a halide (1-30 equiv, preferably 1.1 equiv) isadded. The reaction mixture is heated at about 60-80° C. (preferablyabout 70° C.) for about 1-16 h (preferably about 2 h). After cooling toambient temperature, ice-water is added to the reaction mixture or thereaction mixture is poured into ice water and then extracted with anorganic solvent such as DCM or EtOAc (preferably DCM). The combinedorganic portions are concd under reduced pressure. Alternatively, thecombined organic portions are washed with water, saturated aqueousNaHCO₃, brine and dried over anhydrous Na₂SO₄ or MgSO₄, filtered, andconcd under reduced pressure.

Illustration of General Procedure JJ Preparation #JJ.15-(3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyloxy)pyrazine-2-carbonitrile

To3-ethyl-4-((6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanol(0.098 g, 0.24 mmol, prepared using FF from Preparation #KK.1) in DMF (1mL) was added NaH (0.012 g, 0.29 mmol, 60% dispersion in mineral oil)portionwise. After about 5 min, 2-chloro-5-cyanopyrazine (0.039 g, 0.28mmol, ArkPharm) was added. The reaction mixture was heated at about 70°C. for about 2 h. After cooling to ambient temperature, ice water (2 mL)was added and the mixture was extracted with DCM (3×5 mL). The organiclayers were combined and the solvents were removed under reducedpressure. The residue was purified using silica gel chromatography (12g) eluting with a gradient of 20-80% EtOAc in DCM to give5-(3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyloxy)pyrazine-2-carbonitrile(0.085 g, 69%): LC/MS (Table 1, Method b) R_(t)=2.84 min; MS m/z: 505(M+H)⁺.

General Procedure KK: SEM-Protection

To a pyrrole derivative (preferably 1 equiv) in an organic solvent (suchas THF, 1,4-dioxane, or DMF, preferably 1,4-dioxane) at about 0-40° C.(preferably ambient temperature) is added NaH (60% dispersion in mineraloil) (1-3 equiv, preferably 1.05 equiv) in portions. The reactionmixture is stirred for about 1-60 min (preferably about 30 min). SEM-Cl(1-3 equiv, preferably 1.5 equiv) is then added. After about 15 min-24 h(preferably about 30 min), the solvent is removed and the residue ispartitioned between an organic solvent such as EtOAc and water. Thelayers are separated and the organic solvent is removed under reducedpressure to give the target compound. Alternatively, the reactionmixture is poured slowly into ice water with stirring to provide asuspension. Solids may be collected by filtration and dried to providethe target compound. Also, the filtrate may be partitioned between anorganic solvent (such as EtOAc or DCM) and an aqueous base (such as assaturated aqueous NaHCO₃ or saturated aqueous Na₂SO₄, preferablysaturated aqueous NaHCO₃). The organic portion is separated and concdunder reduced pressure to provide the target compound.

Illustration of General Procedure KK Preparation #KK.11-(2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine

To a suspension of1-(2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]-triazolo[4,3-a]pyrazine(0.323 g, 0.825 mmol, prepared using Z from Preparation #EE.1, A fromExample #1, Step D, HATU, and TEA, B with DIEA, D with NaOH) in1,4-dioxane (2.5 mL) was added NaH (0.035 g, 0.866 mmol, 60% dispersionin mineral oil) in portions. The reaction mixture was stirred at ambienttemperature for about 30 min. SEM-Cl (0.15 mL, 0.83 mmol) was added.After about 30 min, the solvent was removed and the residue waspartitioned between EtOAc (12 mL) and water (2 mL). The organic layerwas separated and concd under reduced pressure. The residue was purifiedusing silica gel chromatography (40 g) eluting with a gradient of 0-60%EtOAc in DCM to give1-(2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine(0.372 g, 86%): LC/MS (Table 1, Method b) R_(t)=2.96 min; MS m/z: 522(M+H)⁺.

General Procedure LL: SEM-Deprotection

To a solution of a N-SEM-protected compound (preferably 1 equiv) in anorganic solvent (such as DMF, 1,4-dioxane, or DCM, preferably DCM) isadded TFA (5-70 equiv, preferably 50 equiv) and the reaction mixture isstirred at about 0-40° C. (preferably ambient temperature) for about1-20 h (preferably about 1-4 h). Additional TFA (5-20 equiv, preferably10 equiv) may be added. The resulting mixture is concd under reducedpressure and the residue is dissolved in an organic solvent such as1,4-dioxane, MeOH or EtOH (preferably 1,4-dioxane). An aqueous base(such as NaOH or NH₄OH, preferably NH₄OH, 30-200 equiv, preferably 120equiv) is added and the reaction mixture is heated at about 30-100° C.(preferably about 60° C.) for about 30 min-10 h (preferably about 30min). The reaction mixture is cooled to ambient temperature, water isadded and the product is isolated by filtration. Alternatively themixture may be partitioned between an organic solvent (such as EtOAc orDCM) and an aqueous base (such as saturated aqueous NaHCO₃ or saturatedaqueous Na₂SO₄, preferably saturated aqueous NaHCO₃). The organicportion is separated and concd under reduced pressure to provide thetarget compound. In some cases an intermediate hydroxymethylsulfonamidemay be isolated.

Illustration of General Procedure LL Preparation #LL.15-(−3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyloxy)pyrazine-2-carbonitrile

To 5-(3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyloxy)pyrazine-2-carbonitrile(0.097 g, 0.19 mmol, Preparation #11.1) in DCM (2.5 mL) was added TFA(0.7 mL, 10 mmol). The reaction mixture was stirred at ambienttemperature for about 1.5 h. The solvents were removed under reducedpressure and the residue was dissolved in 1,4-dioxane (1.3 mL). Ammoniumhydroxide (28-30% aqueous ammonia, 2.5 mL, 24 mmol) was added and thereaction mixture was heated at about 60° C. for about 30 min then cooledto ambient temperature. Water (4 mL) was added and the precipitate wascollected by filtration to give5-(−3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyloxy)pyrazine-2-carbonitrile(0.0628 g, 87%): LC/MS (Table 1, Method b) R_(t)=1.99 min; MS m/z: 375(M+H)⁺.

TABLE LL.1 Examples prepared using General Procedure LL R_(t) min (Table1, m/z ESI + Silyl protected pyrrole Product Ex # Method) (M + H)⁺N-((1S,3R,4S)-3-ethyl-4-(8-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)-N-((2-(trimethylsilyl)ethoxy)methyl) cyclopropanesulfonamide (Preparation #23)

LL.1.1* 1.71 (a) 389 N-((1S,3R,4S)-3-ethyl-4-(8-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)-N-((2-(trimethylsilyl)ethoxy)methyl) cyclopropanesulfonamide (Preparation #23)

LL.1.2* 1.96 (a) 419 N-((1S,3S,4R)-3-(8-cyano-6-((2-(trimethylsilyl)ethoxy)methyl)-6H- pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-4- ethylcyclopentyl) cyclopropanesulfonamide(Preparation #HHH.1)

LL.1.3* 1.64 (b) 400 1-((1S,2R,4R)-2-ethyl-4-(2,2,2-trifluoroethylsulfonyl)cyclopentyl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazine (Preparation #LLL.1)

LL.1.4 1.81 (a) 402 3-fluoro-N-((1S,3R,4S)-3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentyl)propane-1-sulfonamide (prepared using FFFFF fromPreparation #33, GGGGG with Preparation #E.1.1, KKKK with PFPAA, D withNaOH, KK, Y; K with 3-fluoropropane-1-sulfonyl chloride [Hande])

LL.1.5* 1.53 (b) 380 3,3-difluoro-N-((1S,3R,4S)-3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)- 3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentyl)cyclobutane- 1-sulfonamide (prepared usingFFFFF with Preparation #33, GGGGG with Preparation #E.1.1, KKKK withPFPAA, D with NaOH, KK, Y, K with Preparation #34 and DIEA)

LL.1.6* 1.84 (a) 410 3,3,3-trifluoro-N-methyl-N-((1S,3R,4S)-3-methyl-4-(3-((2- (trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentyl)propane-1-sulfonamide (prepared using FFFFF withPreparation #33, GGGGG with Preparation #E.1.1, KKKK with PFPAA, D withNaOH, KK, Y, K with 3,3,3-trifluoropropane-1- sulfonyl chloride(Matrix), S with iodomethane )

LL.1.7* 2.04 429 N-((1S,3R,4S)-3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentyl)azetidine-1-sulfonamide (prepared using FFFFF withPreparation #33, GGGGG with Preparation #E.1.1, KKKK with PFPAA, D withNaOH, KK, Y, ZZ, AAA with azetidine)

LL.1.8* 1.53 375 3-fluoro-N-((1S,3R,4S)-3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentyl)azetidine-1-sulfonamide (prepared using FFFFF withPreparation #33, GGGGG with Preparation #E.1.1, KKKK with PFPAA, D withNaOH, KK, Y, ZZ, AAA with 3- fluoroazetidine hydrochloride [Parkway])

LL.1.9* 1.73 393 2-cyano-N-((1S,3R,4S)-3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8- yl)cyclopentyl)acetamide(prepared using FFFFF with Preparation #33, GGGGG with Preparation#E.1.1, KKKK with PFPAA, D with NaOH, KK, Y, H with cyanoacetic acid)

LL.1.10* 1.61 323 1-((1S,2R,4R)-4-(1H-pyrazol-1-yloxy)-2-ethylcyclopentyl)-6-((2- (trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazine (prepared from Example #35, Step H, using IIII and JJJJ with N- hydroxypyrazole (preparedaccording to Journal of the Chemical Society, Perkin Transactions 1:Organic and Bio- Organic Chemistry (1995), (3), 243- 7).

LL.1.11 1.87 338 (1R,3R,4S)-3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H- pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanecarbonitrile (prepared from Example #35, stepH, using IIII and JJJJ with sodium cyanide)

LL.1.12 1.75 281 1-((1S,2R,4S)-4-(3-cyclopropyl-1H-pyrazol-1-yl)-2-ethylcyclopentyl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H- pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (prepared using JJJJ from Example #35 step I, with sodiumhydride and 5-cyclopropyl-1H-pyrazole (ChemBridge))

LL.1.13 1.98 362 1-((1S,2R,4S)-4-(3-cyclopropyl-1H-pyrazol-1-yl)-2-ethylcyclopentyl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H- pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (prepared from Example #35 step I, using JJJJ with sodiumhydride and 5-cyclopropyl-1H-pyrazole (ChemBridge))

LL.1.14 2.02 362 3-(-3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H- pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyloxy)methyl)- 5-methylisoxazole (Preparation#HHHH.1)

LL.1.15 1.71 (b) 367 4-(2-(3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H- pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentyloxy)ethyl)morpholine (prepared using HHHHfrom Example #35, step H and 4-(2- chloroethyl)morpholine [Beta Pharma]with KOH)

LL.1.16 1.16 (b) 385 1-(4-(2,2-difluoroethoxy)-2-ethylcyclopentyl)-6-((2- (trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazine (prepared using HHHH fromExample #35 step H and 2-bromo-1,1- difluoroethane [Lancaster] with KOH)

LL.1.17 1.78 (b) 336 1-(4-(2,2-difluoroethoxy)-2-ethylcyclopentyl)-6-((2- (trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazine (prepared using HHHH fromExample #35, step H and 2-bromo-1,1- difluoroethane [Lancaster] withKOH)

LL.1.18 1.62 (b) 314 1-(3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H- pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyloxy)-2- methylpropan-2-ol (prepared using HHHHfrom Example #35, step H and 1-chloro-2-methyl-2-propanol with KOH)

LL.1.19 1.61 (b) 344 4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3- e]pyrazin-8-yl)piperidine-1-carboximidamide (prepared using R from 1-(benzyloxycarbonyl)piperidine-4-carboxylic acid (Matrix), S with Example #3 Step E, E with TFA, KKKKwith PFPAA, D with NaOH, KK, DDDDD, EEEEE)

LL.1.20 2.04 (r) 284 8-cyclohexyl-1-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)-3H- imidazo[1,2-a]pyrrolo[2,3-e]pyrazine(prepared using GGG with 8- cyclohexyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine (WO2009152133A1), KK, VVV with2,4,6-trimethyl-1,3,5,2,4,6- trioxatriborinane)

LL.1.21 2.21 (a) 255 t-butyl 2-oxo-2-(4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8- yl)piperidin-1-yl)ethylcarbamate(prepared using R from 1- (benzyloxycarbonyl)piperidine-4- carboxylicacid (Matrix), S from Example #3 Step E, E with TFA, KKKK with PFPAA, Dwith NaOH, KK, DDDDD, H from 2-(t- butoxycarbonylamino)acetic acid)

LL.1.22 2.84 (r) 299 (1S,3R,4S)-3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8- yl)cyclopentanamine (preparedusing X from Example #24 Step H and dibenzylamine, FFFFF, GGGGG fromPreparation #E.1.1, KKKK with PFPAA, D with NaOH, KK, Y)

LL.1.23 1.39 (a) 256 2-(3-((1S,3R,4S)-3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8- yl)cyclopentylamino)oxetan-3-yl)acetonitrile (Preparation YYY.1)

LL.1.24 1.49 (a) 351 N-(2-cyclopropylethyl)-N-((1S,3R,4S)-3-methyl-4-(3-((2- (trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8- yl)cyclopentyl)oxetan-3-amine(prepared using using X from Example #24 Step H and dibenzyl amine,FFFFF, GGGGG from Preparation #E.1.1), KKKK with PFPAA, D with NaOH, KK,Y, X with oxetan-3-one [PharmaBlock], X with 2- cyclopropylacetaldehyde[Anichem])

LL.1.25 1.55 (a) 380 N-(cyclopropylmethyl)-N-((1S,3R,4S)-3-methyl-4-(3-((2- (trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8- yl)cyclopentyl)oxetan-3-amine(prepared using using X from Example #24 Step H and dibenzyl amine,FFFFF, GGGGG from Preparation #E.1.1), KKKK with PFPAA, D with NaOH, KK,Y, X with oxetan-3-one [PharmaBlock], X with cyclopropanecarbaldehyde)

LL.1.26 1.40 (a) 366

General Procedure LL.1: SEM-Deprotection

A N-SEM-protected compound is dissolved or suspended in an organicsolvent (such as DMF, 1,4-dioxane, THF, MeOH, or DCM, preferably DCM).TFA, camphorsulfonic acid, or HCl, preferably TFA (5-70 equiv,preferably 50 equiv) may be added and the reaction mixture is stirred atabout 0-40° C. (preferably ambient temperature) for about 1-20 h(preferably about 1-4 h). Optionally, additional TFA (5-20 equiv,preferably 10 equiv) may be added. The resulting mixture is concentratedunder reduced pressure. Alternatively, the solution or suspension ofSEM-protected material may be treated with a fluoride source such asTBAF or LiBF₄, preferably TBAF (1-20 equiv, preferably 6 equiv).Optionally, a base such as aqueous NaOH, ethylenediamine, or aqueousNH₄OH (1-200 equiv, preferably ethylenediamine, 2 equiv) may be added.The reaction mixture is heated at about 30-100° C. (preferably about 60°C.) for about 30 min −72 h (preferably about 24 h). The reaction mixtureis cooled to ambient temperature. Optionally the volatiles are removedunder reduced pressure. The reaction mixture is worked up using one ofthe following methods. Method 1: The residue is dissolved in an organicsolvent such as 1,4-dioxane, MeOH or EtOH (preferably 1,4-dioxane). Abase such as aqueous NaOH, ethylenediamine, or aqueous NH₄OH (preferablyaqueous NH₄OH, 1-200 equiv, preferably 120 equiv) is added and thereaction mixture is heated at about 30-100° C. (preferably about 60° C.)for about 5 min-10 h (preferably about 30 min). The reaction mixture iscooled to ambient temperature, water is added and the product isisolated by filtration. Method 2: The mixture is partitioned between anorganic solvent (such as EtOAc or DCM) and an aqueous base (such assaturated aqueous NaHCO₃ or saturated aqueous Na₂SO₄, preferablysaturated aqueous NaHCO₃). The organic portion is separated andconcentrated under reduced pressure to provide the target compound.Method 3: Optionally, water, aqueous NaHCO₃, or aqueous NH₄Cl(preferably water) is added. The product may be isolated by filtrationor the mixture may be extracted with an organic solvent (such as EtOAcor DCM). The organics are dried over Na₂SO₄ or MgSO₄, filtered, andconcentrated under reduced pressure to provide the target compound. Insome cases an intermediate hydroxymethylsulfonamide may be isolated.

Illustration of General Procedure LL.1 Preparation #LL.1.1 tert-butyl(trans-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-8-carboxamido)cyclohexyl)methylcarbamate

Ethylenediamine (0.011 mL, 0.16 mmol) was added to a solution oftert-butyl(trans-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-8-carboxamido)cyclohexyl)methylcarbamate(0.043 g, 0.079 mmol, prepared using Z from Preparation #AAAAA.1 andKOH, H with tert-butyl trans-4-aminocyclohexylmethylcarbamate [AMRI],HATU, and TEA) in THF (1 mL). TBAF (1.0 M solution in THF, 0.470 mL,0.470 mmol) was added in one portion. The mixture was heated at about60° C. After about 24 h, the solution was allowed to cool to ambienttemperature and stirred for about 40 h. The volatiles were removed underreduced pressure. The residue was slurried in water (10 mL) andextracted with EtOAc (4×20 mL). The combined organic portions werewashed with brine (10 mL), dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. The residue was purified by silica gelchromatography eluting with a gradient of 2-10% MeOH/DCM to givetert-butyl(trans-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-8-carboxamido)cyclohexyl)methylcarbamate(0.0094 g, 29%): LC/MS (Table 1, Method n) R_(t)=0.55 min; MS m/z: 414(M+H)⁺.

General Procedure MM: Halogenation of an Imidazole

To a solution of an imidazole (preferably 1 equiv) in an organic solvent(such as DCM, MeOH or THF, preferably THF) is added a halogenatingreagent (such as bromine, pyridinium hydrobromide perbromide, NCS, NBS,or NIS) (0.9-1.1 equiv, preferably 1 equiv). The reaction is stirred atabout −20-150° C. (preferably about 0-60° C.) for about 10 min-48 h(preferably about 30 min). The reaction mixture is then partitionedbetween an organic solvent (such as EtOAc, DCM or 1,4-dioxane,preferably EtOAc) and an aqueous base (such as saturated aqueous NaHCO₃or saturated aqueous Na₂CO₃, preferably saturated aqueous NaHCO₃). Theaqueous layer is optionally extracted with additional organic solvent(such as EtOAc or DCM). The combined organic layers may optionally bewashed with brine and concd in vacuo or dried over anhydrous Na₂SO₄ orMgSO₄ and then decanted or filtered prior to concentrating under reducedpressure to give the tareagent, and mercury(II)acetate) in THF (10 mL)at about 0° C. was added a solution of NBS (0.12 g, 0.672 mmol) in THF(2 mL). After about 30 min, the reaction mixture was diluted with EtOAc(20 mL) and saturated aqueous NaHCO₃ (20 mL). The organic layer wasseparated, concd in vacuo, and purified by chromatography on silica gel(40 g) eluting with EtOAc:DCM:heptane (1:1:2) to provide3-bromo-1-cyclohexyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine(0.27 g 83%) as a tan solid: LC/MS (Table 1, Method a) R_(t)=3.12 min;MS m/z 473, 475 (1:1) (M+H)⁺.

Preparation #MM.13-bromo-1-cyclohexyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine

To a solution of1-cyclohexyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (0.27 g,0.67 mmol, prepared using Q from Preparation #13, Lawesson's reagent,and mercury(II)acetate) in THF (10 mL) at about 0° C. was added asolution of NBS (0.12 g, 0.672 mmol) in THF (2 mL). After about 30 min,the reaction mixture was diluted with EtOAc (20 mL) and saturatedaqueous NaHCO₃ (20 mL). The organic layer was separated, concd in vacuo,and purified by chromatography on silica gel (40 g) eluting withEtOAc:DCM:heptane (1:1:2) to provide3-bromo-1-cyclohexyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine(0.27 g 83%) as a tan solid: LC/MS (Table 1, Method a) R_(t)=3.12 min;MS m/z 473, 475 (1:1) (M+H)⁺.

General Procedure NN: Formation of an Amide from a Carboxylic Acid andan Amine with Loss of a Sulfonamide Protecting Group

To mixture of a 1-substituted6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine with a pendantamino group (preferably 1 equiv) and a carboxylic acid (1-2 equiv,preferably 1.5 equiv) in a solvent (such as DMF or THF, preferably DMF)is added a coupling agent such as EDC.HCl or HATU (1.0-2.0 equiv,preferably 1.2 equiv) with an organic base (such as TEA or DIEA, 1-5equiv, preferably 2 equiv). If EDC.HCl is used as the coupling reagent,HOBT (1-3 equiv, preferably 1.2 equiv) is added. After about 1-72 h(preferably about 18 h) at about 20-60° C. (preferably ambienttemperature), water is added and the aqueous layer is extracted with anorganic solvent such as EtOAc or DCM. The combined organic layers aredried over anhydrous Na₂SO₄ or MgSO₄, filtered or decanted, and concdunder reduced pressure. Intermediates and final compounds prepared viathis General Procedure can be optionally purified using one or more ofthe Purification Methods described above.

Illustration of General Procedure NN Example #NN.1.1N-((1-((6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)methyl)cyclobutyl)methyl)-2-cyanoacetamide

To a solution of(1-((6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)methyl)-cyclobutyl)methanamine(0.225 g, 0.548 mmol) (prepared using A from Example #1, Step D,2-(1-(tert-butoxycarbonylamino)cyclobutyl)acetic acid [prepared asdescribed WO9921824A1], EDC.HCl, B with TEA, E with 4.0 M HCl in1,4-dioxane) in DMF (10 mL) was added cyanoacetic acid (0.070 g, 0.822mmol), HOBt (0.101 g, 0.658 mmol), EDC.HCl (0.126 g, 0.658 mmol) andDIEA (0.190 mL, 1.096 mmol) to give a brown solution. The mixture wasstirred at ambient temperature for about 18 h. Water (20 mL) was addedand the mixture was extracted with EtOAc (3×25 mL). The combined organiclayers were dried over anhydrous MgSO₄, filtered, and concd in vacuo.The crude material was purified by flash chromatography on silica geleluting with a gradient of 0-10% MeOH in DCM to giveN-((1-0H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)methyl)cyclobutyl)methyl)-2-cyanoacetamideas an off-white solid (0.030 g, 17%): LC/MS (Table 1, Method a)R_(t)=1.48 min; MS m/z: 324 (M+H)⁺.

TABLE NN.1 Examples prepared using General Procedure NN with cyanoaceticacid R_(t) min (Table 1, m/z ESI+ Amine Product Ex. # Method) (M + H)⁺1-((6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)methyl)cyclobutanamine (prepared using A from Example #1, Step D and2-(1-(tert- butoxycarbonylamino) cyclobutyl)acetic acid [prepared asdescribed in Eur. J. Med. Chem, 1999, 34, 363] EDC•HC1, B with TEA, Ewith HCl)

NN.1.2 1.40 (a) 310General Procedure OO: Cyclization with POCl₃

To a solution of a urea, an amide, or a hydrazide (1-3 equiv, preferably2 equiv) neat or in an organic solvent (for example, 1,4-dioxane) isadded POCl₃ (10-200 equiv, preferably 100 equiv). The mixture is heatedat about 25-100° C. (preferably about 60° C.) for about 1-16 h(preferably about 1-3 h). The reaction mixture is cooled to ambienttemperature and ice is added. Following dissolution, the pH of themixture is adjusted to about 7 with a base such as aqueous NaOH. If theproduct precipitates from the reaction mixture it can be collected byfiltration. Alternatively the product can be extracted into an organicsolvent (such as EtOAc or DCM) and the organic layers may be optionallywashed with aqueous base (such as saturated aqueous NaHCO₃) and/orbrine, dried over anhydrous Na₂SO₄ or MgSO₄, then decanted or filteredprior to concentrating under reduced pressure.

Preparation #OO.1N-((3S,5R)-5-methyl-1-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrrolidin-3-yl)cyclopropanesulfonamide

A flask was charged with(2R,4S)-4-(cyclopropanesulfonamido)-2-methyl-N-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)pyrrolidine-1-carboxamide(0.11 g, 0.207 mmol, prepared using E from Preparation #14 and J fromExample #5 Step C and CDI) and POCl₃ (1.9 mL, 21 mmol). The reactionmixture was heated to about 60° C. resulting in a homogeneous mixture.After about 2 h, the reaction mixture was cooled to ambient temperatureand crushed ice was added. After the ice had melted, 2 N aqueous NaOHwas added until a pH of about 7 was obtained. The resulting precipitatewas collected by filtration and dried in vacuo to provideN-((3S,5R)-5-methyl-1-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrrolidin-3-yl)cyclopropane-sulfonamide(0.10 g, 94%) as a tan solid: LC/MS (Table 1, Method a) R_(t)=2.14 min;MS m/z: 515 (M+H)⁺.

General Procedure OO.1: Cyclization with POCl₃

To a urea, an amide, or a hydrazide, neat or in an organic solvent (suchas 1,4-dioxane, DCE, or toluene), is added POCl₃ (3-200 equiv,preferably 100 equiv). The mixture is heated at about 25-110° C.(preferably about 100° C.) for about 1-16 h (preferably about 1-3 h).The reaction mixture is allowed to cool to ambient temperature. Thereaction mixture may be added to ice or ice may be added. Alternatively,the volatiles may be removed under reduced pressure. Optionally, DCM isadded followed by slow addition of MeOH and then the mixture isconcentrated under reduced pressure. An aqueous layer such as water oraqueous HCl is added and an organic solvent such as 1,4-dioxane may beadded and the solution may be warmed to about 30-110° C. (preferablyabout 100° C.) for about 0.5-6 h (preferably about 3 h). Followingconcentration under reduced pressure, the pH of the mixture may beadjusted with a base such as aqueous NaOH or NaHCO₃ (preferably to aboutpH 7) and an organic solvent such as EtOAc or DCM is added. The productmay be collected by filtration or extracted into an organic solvent(such as EtOAc or DCM). The organic layers may be optionally washed withaqueous base (such as saturated aqueous NaHCO₃) and/or brine, dried overanhydrous Na₂SO₄ or MgSO₄, and then decanted or filtered prior toconcentrating under reduced pressure.

Preparation #OO.1.13-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-amine

To 2-(5-tosyl-5H-pyrrolo[3,2-b]pyrazin-2-ylamino)acetamide (0.845 g,2.45 mmol, prepared using E from Preparation #S.1.1 and HCl) undernitrogen was added POCl₃ (5.0 mL, 54 mmol). After about 15 min, a refluxcondenser was attached and the mixture was warmed to about 100° C. Afterabout 2 h, the solution was allowed to cool to ambient temperature. Themixture was concd under reduced pressure. The residue was slurried inDCM (10 mL) and slowly treated with MeOH (10 mL). The reaction mixturewas stirred for about 5 min then concd under reduced pressure. Theresidue was dissolved in MeOH (20 mL) and then concentrated underreduced pressure. The residue was dissolved in 1,4-dioxane (5 mL) and 2Naqueous HCl (5 mL). The solution was warmed to about 100° C. for about 3h. The solution was allowed to cool to ambient temperature and thevolatiles were removed under reduced pressure. The aqueous mixture wasslurried in saturated aqueous NaHCO₃/water (1:1, 100 mL) and DCM (50mL). The solid was collected by filtration, rinsed with water and DCM,and dried to afford3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-amine (0.343 g, 43%):LC/MS (Table 1, Method n) R_(t)=0.56 min; MS m/z: 328 (M+H)⁺.

General Procedure PP: Reaction of an Amine with an Aryl Boronic Acid

To a solution of a boronic acid (preferably 1-3 equiv) in an organicsolvent (such as DCM or MeCN) is added an organic base, such as DIEA(1-5 equiv, preferably 1 equiv), an inorganic catalyst (such as copper(II) acetate monohydrate (0.1 to 0.5 equiv, preferably 0.25 equiv), anamine (preferably 1 equiv) and a drying reagent (such as 4 Å molecularsieves). The reaction mixture is purged with oxygen (1-5 times,preferably 3 times) and heated at about 20-60° C. (preferably about40-50° C.) for about 1-24 h (preferably about 18 h) under an atmosphereof oxygen. If the reaction does not reach completion, additionalinorganic catalyst (such as copper (II) acetate monohydrate (0.1 to 0.5equiv, preferably 0.25 equiv) may be added. The reaction mixture isallowed to cool to ambient temperature before it is concd under reducedpressure

Illustration of General Procedure PP Preparation #PP.1*3-((1S,3R,4S)-3-methyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)benzonitrile

To a solution of 3-cyanophenylboronic acid (0.143 g, 0.974 mmol) in DCM(4 mL) was added copper (II) acetate monohydrate (0.013 g, 0.122 mmol)and 4 Å molecular sieves. The reaction mixture was purged 3 times withoxygen. A solution of(1S,3R,4S)-3-methyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]-triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine(0.20 g, 0.48 mmol, Preparation #19.2) and DIEA (0.085 mL, 0.487 mmol)in MeCN (1 mL) was added and the reaction mixture was heated at about45° C. for about 18 h. Additional copper (II) acetate monohydrate (0.013g, 0.122 mmol) was added and the reaction mixture was stirred for about4 h. The reaction mixture was filtered through a pad of Celite® andconcd under reduced pressure. The crude material was purified by silicagel chromatography eluting with a gradient of 0-60% EtOAc in DCM to give3-((1S,3R,4S)-3-methyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)benzonitrile(0.16 g, 48%) as a dark brown solid: LC/MS (Table 1, Method c)R_(t)=1.54 min; MS m/z: 512 (M+H)⁺.

General Procedure QQ: Formation of a Urea from an Amine and anIsocyanate

To a flask containing an amine or an amine salt (1 equiv) in an organicsolvent (such as THF, DCM, or MeCN, preferably DCM) is optionally addeda base (such as DIEA or TEA, preferably DIEA, 1-3 equiv, preferably 1equiv) and the reaction mixture is stirred at ambient temperature forabout 0-30 min (preferably about 5 min). An isocyanate (1-5 equiv,preferably 1 equiv) is added and the mixture is stirred at about 10-60°C. (preferably ambient temperature) for about 1-24 h (preferably about18 h). The organic solvent is optionally removed under reduced pressureunless MeCN is used in which case the solvent is preferably removedunder reduced pressure. The crude material can be partitioned between anorganic solvent (such as EtOAc or DCM) and water, an aqueous base (suchas saturated aqueous NaHCO₃) or brine. The layers are separated and theaqueous layer is optionally washed with an organic solvent (such asEtOAc or DCM). The combined organic extracts are dried over anhydrousNa₂SO₄ or MgSO₄, filtered, and concd under reduced pressure to give thetarget compound.

Illustration of General Procedure QQ Example #QQ.1.1*(3R,4R)—N-(2,4-difluorophenyl)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidine-1-carboxamide

A round bottom flask was charged with1-((3R,4R)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazinehydrochloride (0.05 g, 0.17 mmol, Example #5 Step J) and DIEA (0.03 mL,0.17 mmol) in DCM (1.6 mL). The reaction mixture was stirred for about 5min at ambient temperature then 2,4-difluoro-1-isocyanatobenzene (0.02mL, 0.17 mmol) was added and the reaction mixture was stirred at ambienttemperature for about 18 h. The reaction mixture was diluted with DCM (5mL) and washed with water (2 mL). The aqueous layer was back extractedwith DCM (2 mL). The combined organic layers were dried over anhydrousMgSO₄, filtered, and concd under reduced pressure. The material waspurified by RP-HPLC (Table 1, Method e) to afford(3R,4R)—N-(2,4-difluorophenyl)-3-(6H-imidazo[5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidine-1-carboxamide(0.014 g, 20%): LC/MS (Table 1, Method j) R_(t)=1.77 min; MS m/z 411(M+H)⁺.

TABLE QQ.1 Examples prepared from1-((3R,4R)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine hydrochloride (Example #5 Step J) using GeneralProcedure QQ R_(t) min (Table 1, m/z ESI+ Isocyanate Product Example #Method) (M + H)⁺ 2-(4- isocyanatophenyl) acetonitrile

QQ.1.2* 1.69 (b) 414 3-isocyanatobenzonitrile

QQ.1.3* 1.76 (b) 400 4-isocyanatobenzonitrile

QQ.1.4* 1.74 (b) 400General Procedure RR: Formation of a Urea from an Amine, a HeteroarylAmine and Phenyl Chloroformate

To a flask containing a heteroaryl amine (1-6 equiv, preferably 2.1equiv) in an organic solvent or mixture of solvents (such as THF/MeCN,THF, DCM, or MeCN, preferably MeCN), a base such as pyridine, DIEA orTEA, preferably TEA (1-6 equiv, preferably 2 equiv) and DMAP (0.1-0.6equiv, preferably 0.2 equiv) is added phenyl chloroformate (1-6 equiv,preferably 2.0 equiv) at about −5-25° C. (preferably about 0° C.). Thereaction mixture is warmed to ambient temperature and stirred for about1-4 h (preferably about 3 h). The organic solvent is optionally removedunder reduced pressure. The crude material can be partitioned between anorganic solvent such as EtOAc, DCM or Et₂O (preferably Et₂O) and wateror brine. The layers are separated and the organic layer is optionallywashed with water or brine, dried over anhydrous Na₂SO₄ or MgSO₄,filtered, and concd under reduced pressure to give the crude carbamate.The crude carbamate is dissolved in an organic solvent such as MeCN, THFor DMF (preferably MeCN) and added to a solution of amine or amine salt(1-2 equiv, preferably 1 equiv), and a base such as pyridine, TEA orDIEA (preferably DIEA, 1-2 equiv, preferably 1 equiv) in an organicsolvent such as MeCN, THF or DMF (preferably MeCN) and stirred at about25-80° C. (preferably about 70° C.) for about 0.5-48 h (preferably about2-18 h). The solvent is optionally removed under reduced pressure. Thecrude material can be partitioned between an organic solvent (such asEtOAc or DCM) and water, an aqueous base (such as aqueous NaHCO₃) orbrine. The layers are separated and the organic layer is optionallywashed with water, an aqueous base (such as saturated aqueous NaHCO₃)and/or brine, dried over anhydrous Na₂SO₄ or MgSO₄, filtered, and concdunder reduced pressure to give the target compound.

Illustration of General Procedure RR Example #RR.1.1*(3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methyl-N-(pyrimidin-4-yl)piperidine-1-carboxamide

To solution of 4-aminopyrimidine (0.04 g, 0.43 mmol), TEA (0.07 mL, 0.47mmol) and DMAP (0.006 g, 0.05 mmol), in MeCN (1 mL) at about 0° C. wasadded phenyl chloroformate (0.05 mL, 0.41 mmol). The reaction mixturewas warmed to ambient temperature and stirred for about 3 h. To thereaction mixture was added water (2 mL) and Et₂O (5 mL). The organiclayer was separated, washed with water (2 mL), dried over anhydrousMgSO₄, filtered, and concd under reduced pressure to provide the crudecarbamate. The carbamate was dissolved in MeCN (1 mL) and to it wasadded a solution of1-((3R,4R)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazinehydrochloride (0.06 g, 0.21 mmol, Example #5 Step J) and DIEA (0.04 mL,0.21 mmol) in MeCN (1 mL). The reaction mixture was heated to about 70°C. for about 2 h. The solvent was removed under reduced pressure. Thecrude residue was dissolved in DCM (5 mL) and washed with water (2 mL),brine (3 mL), dried over anhydrous MgSO₄, filtered, and concd underreduced pressure. The crude material was purified by RP-HPLC (Table 1,Method e) to give(3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methyl-N-(pyrimidin-4-yl)piperidine-1-carboxamide(0.007 g, 9%): LC/MS (Table 1, Method b) R_(t)=1.40 min; MS m/z 377(M+H)⁺.

TABLE RR.1 Examples prepared from1-((3R,4R)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine hydrochloride (Example #5 Step J) using GeneralProcedure RR R_(t) min (Table 1, m/z ESI+ Heteroaryl amine ProductExample # Method) (M + H)⁺ pyrimidin-2-amine

RR.1.2* 1.29 (b) 377 pyridin-2-amine

RR.1.3* 1.95 (b) 376 pyrazin-2-amine

RR.1.4* 1.41 (b) 377

General Procedure SS: Hydrolysis of an Ester to an Alcohol

A solution of an ester (preferably 1 equiv) in an organic solvent suchas THF, MeOH, or EtOH (preferably MeOH) is added to a base in an organicsolvent (such as NaOH in MeOH) or aqueous base (such as Na₂CO₃ or NaOH)(1-20 equiv, preferably 2-10 equiv). The reaction mixture is stirred atambient temperature for about 1-16 h (preferably about 3 h). The mixtureis partitioned between an organic solvent (such as EtOAc or DCM) and anaqueous base (such as saturated aqueous NaHCO₃ or saturated aqueousNa₂CO₃, preferably saturated aqueous NaHCO₃). The organic layer isseparated, dried over anhydrous Na₂SO₄ or MgSO₄, filtered, and concdunder reduced pressure to provide the target compound.

Illustration of General Procedure SS Preparation #SS.13-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanol

To a solution of NaOH (0.088 g, 2.20 mmol) in MeOH (8 mL) was added asolution of3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylbenzoate (0.158 g, 0.312 mmol, prepared using KK from Preparation #20.2)in MeOH (2 mL). The reaction mixture was stirred at ambient temperaturefor about 3 h. The solvent was removed under reduced pressure and DCM(150 mL) was added. The organic layer was washed with water (5 mL),saturated aqueous NaHCO₃ (15 mL), brine (15 mL), and dried overanhydrous MgSO₄, filtered, and concd under reduced pressure to give3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanol(0.123 g, 98%) as clear oil: LC/MS (Table 1, Method b) R_(t)=2.34 min;MS m/z: 402 (M+H)⁺.

General Procedure TT: Acid-Mediated Conversion of an Ester to aCarboxylic Acid

To a solution of an ester (preferably 1 equiv) in an organic solventsuch as 1,4-dioxane or THF (preferably 1,4-dioxane) is added HCl (0.5-12N, preferably 1-6 N aqueous; 5-100 equiv, preferably 10-20 equiv). Thereaction is heated at about 30-120° C. (preferably about 60° C.) forabout 12-120 h (preferably about 36-72 h). In any case where anadditional acid labile group is present (for example, a Boc group) thisgroup may also be cleaved during the reaction. The reaction mixture isconcd under reduced pressure and the pH is adjusted to about 8 with anaqueous inorganic base such as NaHCO₃ or Na₂CO₃ (preferably saturatedaqueous NaHCO₃) and the aqueous phase is extracted with an organicsolvent such as DCM or EtOAc (preferably EtOAc). The organic extract isoptionally washed with brine, dried over a drying agent such asanhydrous MgSO₄ or Na₂SO₄ (preferably anhydrous MgSO₄) and concd underreduced pressure to yield the target compound.

Illustration of General Procedure TT Preparation #TT.14-(dibenzylamino)-2-methylcyclopentanecarboxylic acid

Ethyl 4-(dibenzylamino)-2-methylcyclopentanecarboxylate (3.65 g, 10.38mmol, Example #7, step H) was dissolved in HCl (6 N aqueous, 20 mL) and1,4-dioxane (50 mL) and the resulting mixture was heated at about 60° C.for about 72 h. The solvents were removed under reduced pressure and theresidue was neutralized by the addition of saturated aqueous NaHCO₃ (40mL) and extracted with EtOAc (50 mL). The organic phase was washed withbrine (40 mL), dried over anhydrous MgSO₄ and concd under reducedpressure to yield 4-(dibenzylamino)-2-methylcyclopentanecarboxylic acid(3.3 g, 98%) as a white amorphous solid: LC/MS (Table 1, Method a)R_(t)=1.66 min; MS m/z 324 (M+H)⁺.

General Procedure UU: Formation of 2,2,2-Trichloroacetimidate

To a mixture of an alcohol (preferably 1 equiv) in an organic solvent(such as Et₂O, heptane or DCM, preferably DCM) at about −20° C. to 30°C. (preferably about 0° C.) is added an aqueous base (such as aqueoussodium hydroxide or potassium hydroxide, preferably aqueous potassiumhydroxide, 1-20 equiv, preferably 10 equiv). A catalytic amount of phasetransfer reagent (preferably tetrabutylammonium hydrogen sulfate,0.01-0.5 equiv, preferably 0.1 equiv) is added followed by2,2,2-trichloroacetonitrile (1-10 equiv, preferably 5 equiv). Thereaction mixture is allowed to warm to ambient temperature and stirredat about 15-60° C. (preferably ambient temperature) for about 5-48 h(preferably about 14 h). The layers are separated and the aqueous layeris extracted with an organic solvent (such as Et₂O, EtOAc or DCM,preferably DCM). The combined organic layers are washed with water, anaqueous base (such as saturated aqueous Na₂CO₃ or NaHCO₃) or brine,dried over anhydrous Na₂SO₄ or MgSO₄, filtered, and concd under reducedpressure. Alternatively, an organic base (such as DBU) may be used asthe base for this reaction. In this case, to a mixture of an alcohol(preferably 1 equiv) in an organic solvent (such as Et₂O, heptane orDCM, preferably DCM) at about −20° C. to 30° C. (preferably about 0° C.)is added 2,2,2-trichloroacetonitrile (1-10 equiv, preferably 5 equiv),followed by an organic base preferably DBU (0.2-1 equiv, preferablyabout 0.4 equiv). The reaction mixture is stirred at about −20-30° C.(preferably about 0° C.) for about 0.5-10 h (preferably about 1 h) thenconcd.

Illustration of General Procedure UU Preparation #UU.1 ethyl2-ethyl-4-(2,2,2-trichloro-1-iminoethoxy)cyclopentanecarboxylate

To ethyl 2-ethyl-4-hydroxycyclopentanecarboxylate (3.52 g, 18.9 mmol,Preparation #P.1) in DCM (21 mL) at about 0° C. was added aqueouspotassium hydroxide (50%, 21 mL, 189 mmol), tetrabutylammonium hydrogensulfate (0.64 g, 1.891 mmol) and 2,2,2-trichloroacetonitrile (9.5 mL, 95mmol). The reaction mixture was allowed to warm to ambient temperatureand stirred at ambient temperature for about 14 h. The layers wereseparated and the aqueous layer was extracted with DCM (4×60 mL). Thecombined organic layers were washed with water (2×50 mL), brine (60 mL),dried over anhydrous MgSO₄, filtered and concd under reduced pressure.The material was purified by silica gel chromatography eluting with agradient of 15-50% EtOAc in heptane to afford ethyl2-ethyl-4-(2,2,2-trichloro-1-iminoethoxy)cyclopentanecarboxylate (2.80g, 45%) as a colorless oil: LC/MS (Table 1, Method b) R_(t)=2.91 min; MSm/z: 330 (M+H)⁺.

General Procedure VV: TBDMS-Protection of an Alcohol

To a mixture of an alcohol (preferably 1 equiv) in an organic solvent(preferably DMF) is added TBDMS-Cl (1-5 equiv, preferably 1.2 equiv) andimidazole (1-10 equiv, preferably 2.5 equiv). The reaction mixture isstirred at about 10-60° C. (preferably ambient temperature) for about1-24 h (preferably about 3 h). An organic solvent is added (such asheptane, hexane or pentane, preferably heptane). The layers areseparated and the bottom layer (DMF layer) is extracted with an organicsolvent (such as pentane, hexane or heptane, preferably heptane). Thecombined extracts are washed with water, an aqueous base (such assaturated aqueous NaHCO₃) or brine, dried over anhydrous Na₂SO₄ orMgSO₄, filtered, and concd under reduced pressure.

Illustration of General Procedure VV Preparation #VV.1 Ethyl4-(tert-butyldimethylsilyloxy)-2-ethylcyclopentanecarboxylate

To a solution of ethyl 2-ethyl-4-hydroxycyclopentanecarboxylate (4.97 g,26.7 mmol, prepared using II from Preparation #P.1, SS with NaOH)) inDMF (9 mL) was added TBDMS-Cl (4.83 g, 32.1 mmol) and imidazole (4.55 g,66.8 mmol). The reaction mixture was stirred at ambient temperature forabout 3 h. Heptane (30 mL) was added. The layers were separated and thebottom layer (DMF layer) was extracted with heptane (3×30 mL). Thecombined organic extracts were washed with water (2×30 mL), brine (30mL), dried over anhydrous MgSO₄, filtered and concd under reducedpressure. The material was purified by silica gel chromatography elutingwith a gradient of 0-15% EtOAc in heptane to afford ethyl4-(tert-butyldimethylsilyloxy)-2-ethylcyclopentanecarboxylate (5.16 g,64%) as a colorless oil: ¹H NMR (400 MHz, CDCl₃) δ 4.45 (m, 1H), 4.11(m, 2H), 3.08 (m, 1H), 2.34 (m, 1H), 2.18 (m, 1H), 1.75 (m, 2H), 1.57(m, 1H), 1.41 (m, 1H), 1.25 (m, 3H), 1.10 (m, 1H), 0.90 (m, 3H), 0.87(s, 9H), 0.03 (s, 6H).

General Procedure WW: Formation of a Ketal

To a solution of a ketone (preferably 1 equiv), an organic solvent (suchas DCM, DCE, or toluene, preferably DCM), a diol such as ethylene glycol(1-3 equiv, preferably 2 equiv), and an acid such as p-toluenesulfonicacid monohydrate (0.1-0.5 equiv, preferably 0.2 equiv) is optionallyadded a dehydrating agent such as triethylorthoformate ortrimethylorthoformate (preferably triethylorthoformate, 1-4 equiv,preferably 1.5 equiv) The reaction mixture is stirred at rt to about110° C. (preferably rt in the presence of a dehydrating agent such astriethylorthoformate or preferably about 110° C. in the absence of adehydrating agent) for about 16-96 h (preferably about 24 h). If heated,the reaction mixture is cooled to rt. The reaction mixture is worked upusing one of the following methods. Method 1: Water is added to thereaction mixture, the layers are separated, and the organic solution isoptionally washed with brine, dried over anhydrous Na₂SO₄ or MgSO₄, thendecanted or filtered prior to concentrating under reduced pressure.Method 2: The reaction mixture is concd under reduced pressure andpurified directly.

Illustration of General Procedure WW Preparation #WW.1 ethyl2-ethyl-4-oxocyclopentanecarboxylate

A round bottom flask was charged with ethyl2-ethyl-4-oxocyclopentanecarboxylate (1.5 g, 8.1 mmol, Example #22, StepB) in DCM (22 mL). To the flask were added ethylene glycol (0.91 mL, 16mmol), triethylorthoformate (2.0 mL, 12 mmol), and p-toluenesulfonicacid monohydrate (0.31 g, 1.6 mmol). The reaction mixture was stirred atrt for about 24 h. The solution was concd under reduced pressure to givea brown oil that was dissolved in minimal EtOAc and purified by silicagel chromatography (Silicycle 25 g column) eluting with a gradient of0-50% EtOAc in heptane to give ethyl2-ethyl-4-oxocyclopentanecarboxylate (1.6 g, 83%) as a light yellow oil:LC/MS (Table 1, Method c) MS m/z 229 (M+H); ¹H NMR (CDCl₃) δ 4.14 (q,2H), 3.90 (m, 4 H), 2.99 (q, 1H), 2.32-2.27 (m, 1H), 2.26-2.11 (m, 1H),2.05-1.99 (m, 1H), 1.96-1.91 (m, 1H), 1.83-1.78 (m, 1H), 1.46-1.39 (m,1H), 1.31-1.24 (m, 1H), 1.26 (t, 3H), 0.90 (t, 3H).

General Procedure XX: Palladium Catalyzed Coupling of a Hydrazone

To a mixture of a substituted5-chloro-4-(hydrazonomethyl)-1H-pyrrolo[2,3-b]pyridine (1 equiv) in anorganic solvent (preferably NMP) is added a base (such as K₂CO₃ orsodium tert-butoxide, preferably sodium tert-butoxide [1-4 equiv,preferably 2.5 equiv]) a palladium catalyst (preferably palladiumacetate [0.01-0.2 equiv, preferably 0.1 equiv]) and a ligand (preferably(R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyl-di-tert-butylphosphine[0.01-0.2 equiv, preferably 0.1 equiv]). The reaction mixture is heatedthermally or in a microwave (preferably in a microwave) at about100-165° C. (preferably 150° C. for about 10 min 6 h (preferably about 2h)). The reaction mixture is filtered through a pad of Celite® washingwith an organic solvent (such as EtOAc or DCM, preferably EtOAc) andconcd under reduced pressure to remove wash solvent. The crude materialis optionally resubmitted to the reaction conditions. Then the crudematerial is partitioned between an organic solvent (such as EtOAc orDCM, preferably EtOAc) and water and the aqueous phase is extracted withan organic solvent (such as EtOAc or DCM, preferably EtOAc), washed withwater and/or brine, dried over anhydrous MgSO₄, filtered and concd underreduced pressure.

Illustration of General Procedure XX Preparation #XX.1 tert-butylbenzyl(4-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine-1-yl)bicyclo[2.2.2]octan-1-yl)carbamate

A microwave reaction vial was charged with tert-butylbenzyl(4-((5-chloro-1H-pyrrolo[2,3-b]pyridin-4-)(hydrazono)methyl)bicyclo[2.2.2]octan-1-yl)carbamate(0.700 g, 1.38 mmol, Example #29 Step G) and NMP (11 mL). Sodiumtert-butoxide (0.331 g, 3.44 mmol), palladium acetate (0.031 g, 0.138mmol) and(R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyl-di-tert-butylphosphine(0.076 g, 0.138 mmol) were each added sequentially. The reaction mixturewas heated in a Biotage microwave at about 150° C. for about 2 h (250psi maximum pressure, 1 min ramp, 150 max watts). The reaction mixturewas filtered through a pad of Celite® washing with EtOAc (about 15 mL),and the EtOAc was removed under reduced pressure. The remaining materialwas transferred to a microwave vial and sodium tert-butoxide (0.331 g,3.44 mmol), palladium acetate (0.031 g, 0.138 mmol) and(R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]-ethyl-di-tert-butylphosphine(0.076 g, 0.138 mmol) were added. The reaction mixture was heated in aBiotage microwave at about 160° C. for about 2 h (250 psi maximumpressure, 1 min ramp, 150 max watts). The reaction mixture was through apad of Celite® washing with EtOAc (about 20 mL). Water (15 mL) was addedand the layers were separated. The aqueous layer was extracted withEtOAc (2×10 mL) and the combined organics were washed with water (3×10mL) and brine (5×15 mL), dried over anhydrous MgSO₄, filtered and concdunder reduced pressure. The remaining dark residue was purified bysilica gel chromatography eluting with a gradient of 10-100% EtOAc inheptane to give tert-butylbenzyl(4-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine-1-yl)bicyclo[2.2.2]octan-1-yl)carbamatewith 0.5 eq EtOAc as an excipient (0.281 g, 39.5%) as a light brownsolid: LC/MS (Table 1, Method b) R_(t)=2.57 min; MS m/z: 472 (M+H)⁺.

General Procedure YY: Michael Addition of an Amine, Amine Salt orHeterocycle to an all-Unsaturated Sulfonamide

To a mixture of an α,β-unsaturated sulfonamide (1-3 equiv, preferably1.0 equiv) and an amine, amine salt or heterocycle (1-10 equiv,preferably 4 equiv) in an organic solvent or mixture of solvents (suchas THF, n-PrOH, water, EtOH, THF/PrOH, THF/EtOH, preferably n-PrOH) isoptionally added a base (such as DIEA or TEA 0-25 equiv, preferably DIEA10-20 equiv). The mixture is stirred at about 25-100° C. (preferablyabout 60-80° C.) for about 2-72 h (preferably about 18-20 h). In caseswhere the reaction does not proceed to completion as monitored by LC/MS,HPLC, and/or TLC; additional amine, amine salt or heterocycle (1-10equiv, preferably 2 equiv) and/or a cosolvent (such as EtOH) may beadded. The reaction is continued at about 25-100° C. (preferably about80° C.) for about 1-24 h (preferably about 1-2 h). In cases where thereis a base-labile protecting group present (for example, a tosyl), thecompound may be deprotected. The reaction mixture is allowed to reachambient temperature and the organic solvent is optionally removed underreduced pressure. The crude material can be partitioned between anorganic solvent (such as EtOAc or DCM) and water, an aqueous base (suchas saturated aqueous NaHCO₃) or brine. The layers are separated and theorganic layer is optionally washed with water, an aqueous base (such assaturated aqueous NaHCO₃) or brine, dried over anhydrous Na₂SO₄ orMgSO₄, filtered, and concd under reduced pressure to give the targetcompound.

Illustration of General Procedure YY Example #YY.1.1*2-(4-cyano-1H-pyrazol-1-yl)-N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)ethanesulfonamide

A mixture ofN-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)ethenesulfonamide(0.065 g, 0.13 mmol, prepared using K.1 from Example #8 Step M and2-chloroethanesulfonyl chloride with TEA), DIEA (0.30 mL, 1.7 mmol) and1H-pyrazole-4-carbonitrile (0.047 g, 0.51 mmol, American CustomChemicals Corp) in n-PrOH (2.0 mL) was stirred for about 2 h at about60° C. then at about 80° C. for about 18 h. The reaction mixture wascooled to ambient temperature and concd under reduced pressure. Thecrude residue was dissolved in DCM (10 mL), washed with saturated NaHCO₃(5 mL), dried over anhydrous MgSO₄, filtered, and concd under reducedpressure. The crude material was purified by silica gel chromatographyeluting with a gradient of 0-5% MeOH in DCM to give2-(4-cyano-1H-pyrazol-1-yl)-N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)ethanesulfonamide(0.024 g, 42%): LC/MS (Table 1, Method b) R_(t)=1.63 min; MS m/z: 454(M+H)⁺.

TABLE YY.1 Examples prepared fromN-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-2-(1H-1,2,4-triazol-1-yl)ethanesulfonamide(prepared using K.1 from Example #8 Step M and 2-chloroethanesulfonylchloride with TEA) using General Procedure YY (Table 1, Method) R_(t)min m/z ESI+ Amine Structure Ex. # (method) (M + H)⁺ 1H-1,2,4-triazole

YY.1.2* 1.41 (b) 430

General Procedure ZZ: Formation of an Oxazolidinone Sulfonourea

To a mixture of an amine or an amine salt (1 equiv) and 2-chloroethylchlorosulfonylcarbamate (prepared as detailed in Bioorg. Med. Chem.Lett., 2006 16, 3367-3370)(1-3 equiv, preferably 1 equiv) in an organicsolvent (preferably DCM) is added a base (such as DIEA or TEA,preferably TEA [2-5 equiv, preferably 3 equiv]) and optionally DMAP (1-3equiv, preferably 1 equiv) and stirred at ambient temperature for about10 min 6 h (preferably about 1 h). The solvent is removed under reducedpressure. In cases where DMAP is used, the crude material can bepartitioned between an organic solvent (such as EtOAc or DCM) and wateror brine, dried over anhydrous MgSO₄, filtered and concd under reducedpressure.

Illustration of General Procedure ZZ Preparation #ZZ.1*N-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-2-oxooxazolidine-3-sulfonamide

To a mixture of 2-chloroethyl chlorosulfonylcarbamate (prepared asdetailed in Bioorg. Chem. Lett., 2006 16, 3367-3370; 0.052 g, 0.236mmol) and(1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine(0.100 g, 0.236 mmol, Example #8 Step M) in DCM (2.4 mL) was added TEA(0.098 mL, 0.71 mmol) and the reaction mixture was stirred at ambienttemperature for about 1 h. The reaction mixture was concd under reducedpressure to giveN-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-2-oxooxazolidine-3-sulfonamide(0.098 g, 65%) as a light brown solid: LC/MS (Table 1, Method a)R_(t)=2.18 min; MS m/z 574 (M+H)⁺.

General Procedure AAA: Formation of a Sulfonylurea from an OxazolidinoneSulfonourea

To a solution of an oxazolidinone (preferably 1 equiv) in an organicsolvent (preferably MeCN) is added an amine or a hydrochloride salt ofan amine (1-2 equiv, preferably 1.5 equiv) and an organic base, such asTEA or DIEA (1-4 equiv, preferably 2 equiv). The reaction is irradiatedin the microwave at about 100-150° C. (preferably 120° C.) for about0.5-1 h (preferably 0.5 h). The reaction mixture is cooled to ambienttemperature and is optionally concd under reduced pressure to give aresidue. The reaction mixture or residue is optionally partitionedbetween an organic solvent (such as DCM or EtOAc, preferably EtOAc),water, an aqueous solution (such as saturated aqueous NaHCO₃ orsaturated aqueous ammonium chloride (preferably saturated aqueousammonium chloride) or brine. The layers are separated and the organiclayer is dried over anhydrous Na₂SO₄ or MgSO₄, filtered, and concd underreduced pressure to give a sulfonylurea.

Illustration of General Procedure AAA Preparation #AAA.1*(R)—N-((1S,3R,4S)-3-methyl-4-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentyl)-2-(trifluoromethyl)pyrrolidine-1-sulfonamide

To a solution ofN-((1S,3R,4S)-3-methyl-4-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentyl)-2-oxooxazolidine-3-sulfonamide(0.200 g, 0.261 mmol, prepared from5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride(WO2009152133) and (1S,2R,4S)-4-acetamido-2-methylcyclopentanecarboxylicacid [prepared from ethyl 4-amino-2-methyl-cyclopentanecarboxylate(WO2009152133) using G, AA, and Z] using H, OO, BB, and ZZ) and(R)-2-trifluoromethylpyrrolidine (0.055 g, 0.392 mmol) in MeCN (1.4 mL)was added TEA (0.073 mL, 0.523 mmol). The reaction was irradiated in aCEM microwave at about 120° C. for about 0.5 h. The reaction mixture wascooled to ambient temperature and concd under reduced pressure to afforda residue. The crude material was purified by silica gel chromatographyeluting with a gradient of 0-70% EtOAc in DCM to afford(R)—N—((1S,3R,4S)-3-methyl-4-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentyl)-2-(trifluoromethyl)pyrrolidine-1-sulfonamide(0.12 g, 75%, 72% purity) as an off-white solid: LC/MS (Table 1, Methoda) R_(t)=2.79 min; MS m/z: 611 (M+H)⁺.

General Procedure BBB: Reduction of a Nitro Group

To a solution of a nitro-containing compound (preferably 1 equiv) in anorganic solvent (preferably EtOH) is added tin (II) chloride dihydrate(1-3 equiv, preferably 1 equiv) and the reaction is stirred at about25-80° C. (preferably at about 75° C.) for about 0.5-24 h (preferablyabout 1-2 h). Optionally, additional portions of tin (II) chloridedihydrate (1-5 equiv, preferably 2 equiv) can be added to the reactionmixture and heating can be continued for about 0.5-24 h (preferablyabout 5-14 h). The reaction mixture is concd under reduced pressure. Thecrude mixture may be diluted with an organic solvent (for example, EtOAcor DCM) and aqueous base (such as 1 N NaOH or saturated aqueous NaHCO₃).The layers are separated and the aqueous layer is extracted with anorganic solvent (such as EtOAc and/or DCM). The combined organic layersare optionally washed with brine, dried over anhydrous MgSO₄, filteredand concd under reduced pressure.

Illustration of General Procedure BBB Preparation #BBB.1N-4-cyclohexyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine-4,5-diamine

To a mixture ofN-cyclohexyl-5-nitro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-amine (0.111 g,0.268 mmol, prepared using K.1 from Example #21 Step D with4-methylbenzene-1-sulfonyl chloride, L with cyclohexylamine) in EtOH(2.5 mL) was added tin (II) chloride dihydrate (0.060 g, 0.268 mmol).The reaction mixture was heated at about 75° C. for about 75 min. Tin(II) chloride dihydrate (0.030 g, 0.134 mmol) was added and the reactionmixture was heated at about 75° C. for about 5 h. Additional tin (II)chloride dihydrate (0.060 g, 0.268 mmol) was added and the reactionmixture was heated at about 75° C. for about 14 h. The solvent wasremoved under reduced pressure. The residue was diluted with EtOAc (25mL) and washed with saturated aqueous NaHCO₃ (25 mL) and brine (25 mL).The organic portion was separated. The aqueous portion was extractedwith EtOAc (3×25 mL). The organic extracts were combined, dried overMgSO₄, filtered, and concd under reduced pressure to giveN-4-cyclohexyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine-4,5-diamine (0.081 g,79%) as a brown oil: LC/MS (Table 1, Method n) R_(t)=0.82 min; MS m/z385 (M+H)⁺.

General Procedure CCC: Formation of an Amide

To a mixture of an amine or amine salt (1 equiv) in an organic solvent(for example, DCM or THF, preferably DCM) at about 0-25° C. (preferably0° C.) is added and organic base (TEA or DIEPA, preferably TEA) (neat oras a solution in an organic solvent (preferably DCM)), 1-3 equiv(preferably 1 equiv) and an acylating agent (for example, an anhydrideor an acid chloride) (preferably an anhydride) (neat or as a solution inan organic solvent (preferably DCM)), 1-3 equiv (preferably 1 equiv).The reaction mixture is stirred at ambient temperature for about 5 min 6h (preferably about 10 min). The reaction mixture is optionally washedwith saturated aqueous NaHCO₃, water, or brine, dried over MgSO₄,filtered, and concd under reduced pressure.

Illustration of General Procedure CCC Preparation #CCC.1N-(4-(cyclohexylamino)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,2,2-trifluoroacetamide

To a 0° C. solution ofN-4-cyclohexyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine-4,5-diamine(Preparation #BBB.1, 0.080 g, 0.208 mmol) in DCM (2.0 mL) was added TEA(2 M in DCM, 0.104 mL, 0.208 mmol) and TFAA (2 M in DCM, 0.104 mL, 0.208mmol). The reaction mixture was stirred for about 10 min. The reactionmixture was washed with saturated aqueous NaHCO₃ (2 mL) and water (2mL), dried over anhydrous MgSO₄, filtered and concd under reducedpressure to giveN-(4-(cyclohexylamino)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,2,2-trifluoroacetamidewith 40 mol % dichloromethane as an excipient (0.089 g, 83%, 90% purity)as a brown solid: LC/MS (Table 1, Method n) R_(t)=0.88 min; MS m/z 481(M+H)⁺.

General Procedure DDD: Cyclization to Form a Fused Imidazole

To a solution of a diamine (preferably 1 equiv) in an organic solventsuch as DMF, DCM, 1,4-dioxane, or MeOH (preferably MeOH) is added thecorresponding cyclization reagent such as TMOF (1-10 equiv, preferably1-2 equiv.). (A catalytic amount of acid, such as TsOH (0.005-0.5 equiv,preferably 0.01 equiv) is optionally added to the reaction mixture whenTMOF is used). Alternatively, a solution of an ortho-substitutedamidoaminoaryl or heteroaryl compound (preferably 1 equiv) is cyclizedin an organic solvent such as DMF or THF using a dehydrating agent suchas TPP, POCl₃ or HCl (5-100 equiv, preferably 10 equiv of TPP). Thereaction mixture is heated at about 25-120° C. (preferably about 65° C.)for about 1-24 h (preferably about 12-16 h), cooled to ambienttemperature and optionally concd under reduced pressure to give aresidue. The residue is partitioned between an organic solvent (such asDCM or EtOAc, preferably EtOAc), water, an aqueous base (such assaturated aqueous NaHCO₃) and/or brine. The layers are separated and theorganic layer is optionally washed with water, an aqueous base (such assaturated aqueous NaHCO₃) and/or brine, dried over anhydrous Na₂SO₄ orMgSO₄, filtered, and concd under reduced pressure.

Illustration of General Procedure DDD Preparation #DDD.1N-(3-ethyl-4-(6-tosylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclopentyl)cyclopropanesulfonamide

To a solution ofN-(3-(5-amino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-4-ethylcyclopentyl)cyclopropanesulfonamide(0.095 g, 75% purity, 0.142 mmol, prepared using L from Preparation #27and Preparation #OOO.1 with DIEA, K.1 with TsCl and NaH, and BBB) andTMOF (0.016 mL, 0.147 mmol) in MeOH (3.09 mL) was addedtoluene-4-sulfonic acid hydrate (0.0003 g, 0.0015 mmol). The reactionwas heated at about 65° C. for about 14 h. The reaction was cooled toambient temperature and concd under reduced pressure to give a crudesolid. The solid was dissolved in EtOAc (10 mL) and was washed withsaturated aqueous NaHCO₃ (5 mL), water (5 mL), and brine (5 mL). Theorganic portion was separated and dried over anhydrous MgSO₄, filtered,and concd under reduced pressure to affordN-(3-ethyl-4-(6-tosylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclopentyl)cyclopropanesulfonamide(0.075 g, 99%) as a yellow solid: LC/MS (Table 1, Method a) R_(t)=2.15min; MS m/z: 514 (M+H)⁺.

General Procedure EEE: Formation of a Sulfonyl Chloride

To a solution of a sulfonic acid or the potassium salt of a sulfonate(preferably 1 equiv) in thionyl chloride (2-30 equiv, preferably 20-25equiv) is added DMF (0.01-0.10 equiv, preferably 0.09 equiv). Thereaction is heated at about 50-100° C. (preferably about 80° C.) forabout 8-24 h (preferably about 12-16 h). The reaction mixture is cooledto 0-25° C. (preferably about 0° C.) and is diluted with water. Thereaction mixture is partitioned between an organic solvent (such as DCMor EtOAc) and water or brine. The layers are separated and the organiclayer is optionally washed with water and/or brine, dried over anhydrousNa₂SO₄ or MgSO₄, filtered, and concd under reduced.

Illustration of General Procedure EEE Preparation #EEE.11-ethylcyclopropane-1-sulfonyl chloride

To a mixture of potassium 1-ethylcyclopropane-1-sulfonate (0.420 g, 2.23mmol, Preparation #JJJ.1) in thionyl chloride (3.58 mL, 49.1 mmol) wasadded DMF (0.016 mL, 0.20 mmol). The reaction was heated at about 80° C.for about 16 h. The reaction was cooled to 0° C. before the slowaddition of water (10 mL). The reaction mixture was diluted with DCM (20mL). The layers were separated and the aqueous portion was extractedwith DCM (3×10 mL). The combined organic layers were separated, driedover anhydrous MgSO₄, filtered, and concd under reduced pressure toafford crude 1-ethylcyclopropane-1-sulfonyl chloride (0.52 g, 83% yield,60% purity) as an orange oil: ¹H NMR (400 MHz, DMSO) d 2.09 (q, J=7.4,2H), 1.62-1.60 (m, 2H), 1.45-1.39 (m, 2H), 0.91 (t, J=7.5, 3H).

General Procedure FFF: Generation of an Ether Under Reductive Conditions

To a solution of a TBDMS ether (1.0 equiv) in MeCN at ambienttemperature is added triethyl silane (1-2 equiv preferably 1.5 equiv),and bismuth (III) bromide (0.05-0.2 equiv, preferably 0.06 equiv). Thereaction is stirred at about 25-60° C. (preferably about 25° C.) forabout 0.5-5 min (preferably 1-3 min). To the reaction mixture is addedan aldehyde or ketone (1-6 equiv, preferably 1.5 equiv) that can beoptionally dried over anhydrous Na₂SO₄ or MgSO₄. In cases where thereaction does not proceed to completion as monitored by TLC, additionaltriethyl silane (1-2 equiv preferably 1.5 equiv) and/or bismuth (III)bromide (0.05-0.2 equiv, preferably 0.06 equiv) and/or aldehyde orketone (1-6 equiv, preferably 1.5 equiv) can be added. The reaction iscontinued at about 25-60° C. (preferably about 25° C.) for about 15min-24 h (preferably about 1 h). The reaction is worked up using one ofthe following methods. Method 1: The reaction mixture is filteredthrough a pad of Celite®. The pad of Celite® can be rinsed withadditional organic solvent (preferably heptane or MeCN) and the filtrateis concd under reduced pressure. Method 2: The reaction mixture isfiltered through an Acrodisc® and the filtrate is concd under reducedpressure.

Illustration of General Procedure FFF Preparation #FFF.1 ethyl2-ethyl-4-(tetrahydro-2H-pyran-4-yloxy)cyclopentanecarboxylate

To a solution of ethyl4-(tert-butyldimethylsilyloxy)-2-ethylcyclopentanecarboxylate (0.200 g,0.666 mmol, Example #22 Step D) in MeCN (4.5 mL) was addedtriethylsilane (0.160 mL, 1.00 mmol) and bismuth(III) bromide (0.020 g,0.045 mmol). The reaction mixture was stirred at ambient temperature forabout 1 min followed by dropwise addition of dihydro-2H-pyran-4(3H)-one(0.100 g, 0.998 mmol). The reaction mixture was stirred at ambienttemperature for about 15 min. The reaction was filtered through anAcrodisc® and the solvent was removed under reduced pressure. The crudematerial was purified by silica gel chromatography using a gradient of10-100% EtOAc in heptane to give ethyl2-ethyl-4-(tetrahydro-2H-pyran-4-yloxy)cyclopentanecarboxylate (0.253 g,94%) as a colorless oil; ¹H NMR (400 MHz, CDCl₃) δ 4.13 (q, J=7.1, 2H),4.05-3.98 (m, 1H), 3.98-3.88 (m, 2H), 3.58-3.47 (m, 1H), 3.46-3.36 (m,2H), 2.80 (q, J=8.5, 1H), 2.16 (dt, J=13.3, 7.7, 1H), 2.09-1.93 (m, 3H),1.90-1.81 (m, 2H), 1.62-1.49 (m, 3H), 1.43 (ddd, J=11.1, 7.4, 5.2, 1H),1.33-1.22 (m, 4H), 0.92-0.83 (m, 3H).

General Procedure GGG: Iodination of a Pyrrole Based Heterocycle

To a pyrrole based heterocycle (preferably 1 equiv) in an organicsolvent such as DMF is added a base such as KOH (1-10 equiv, preferably3 equiv) at about 0° C. to 40° C. (preferably at ambient temperature)and the mixture is stirred for about 2-45 min (preferably about 5 min).Iodine (0.95-1.2 equiv, preferably 1.0 equiv) is added in small portionsand the mixture is stirred for 10-100 min. (preferably about 30 min).The mixture is added drop-wise into saturated aqueous ammonium chloride(10 mL for every 1 mL of DMF used) and the target compound is collectedby filtration, washed with additional water and dried.

Illustration of General Procedure GGG Preparation #GGG.1N-((1S,3R,4S)-3-ethyl-4-(8-iodo-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide

To a solution ofN-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide(0.396 g, 1.06 mmol, prepared as detailed in WO2009152133) in DMF (20mL) was added KOH (0.190 g, 3.38 mmol). The mixture was stirred at rtfor 5 min. Iodine (0.268 g, 1.058 mmol) was added in small portions andthe reaction mixture was stirred at rt for 30 min. The mixture was addeddropwise into a saturated aqueous ammonium chloride (200 mL). Theprecipitate was collected by filtration, washed with water, and dried togiveN-((1S,3R,4S)-3-ethyl-4-(8-iodo-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide(0.494 g, 93%) as an off-white solid: LC/MS (Table 1, Method a)R_(t)=1.83 min; MS m/z 501 (M+H)⁺.

General Procedure GGG.1: Iodination, Chlorination or Bromination of aPyrrole Based Heterocycle

To a pyrrole based heterocycle (preferably 1 equiv) in an organicsolvent such as DMF, THF, MeCN, MeOH, AcOH, CHCl₃, or DCM (preferablyDMF) is optionally added a base such as TEA, NaOAc, K₂CO₃, or KOH (1-10equiv) at about 0-40° C. (preferably at 0° C.) and the mixture isstirred for about 2-45 min (preferably about 5 min). A halogen sourcesuch as I₂, Br₂, NBS, pyridinium tribromide, NCS, or NIS (0.95-1.2equiv, preferably 1.0 equiv) is added portionwise, dropwise neat, or asa solution in a solvent such as DMF. If cooling the ice bath is removedand the mixture is stirred for about 0.1-2 h (preferably about 40 min)at rt. Optionally, a reagent such as sodium thiosulfate or sodiumbisulfite as a solution in water may be added or the reaction mixture isadded to the solution and the reaction mixture stirred for about 5-60min (preferably about 30 min). The mixture may be diluted with or addedinto water or saturated aqueous NH₄Cl (preferably using 10 mL of waterper 1 mL of DMF). The target compound may be collected by filtration orextracted using an organic solvent such as EtOAc or DCM, dried overNa₂SO₄ or MgSO₄, filtered, and concentrated under reduced pressure.

Illustration of General Procedure GGG.1 Preparation #GGG.1.18-iodo-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine

A solution of 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.500 g,3.14 mmol, prepared using D from Preparation #BBBBB.1 and NaOH) and DMF(16 mL) under nitrogen was cooled to about 0° C. The mixture was stirredfor about 5 min. N-Iodosuccinimide (0.707 g, 3.14 mmol) was added. Afterabout 40 min, 5% aq. sodium thiosulfate (10 mL) was added. The cold bathwas removed. After stirring for about 30 min, water (15 mL) was added.The solid was collected by filtration. The filter cake was washed withwater (2×5 mL). The aqueous layer was extracted with EtOAc (4×50 mL).The combined organics were dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. The residue was slurried in water (10 mL) andthen filtered, rinsing with water (2×1 mL). The solid was dried in vacuoto afford a brown solid (0.689 g) containing an approximate 4:1 ratio ofmono- to di-iodinated material.8-iodo-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.506 g, 57%):LC/MS (Table 1, Method n) R_(t)=0.39 min; MS m/z 286 (M+H)⁺.

General Procedure HHH: Cyanation of a Heterocycle

To a solution of a heteroaryl halide (preferably 1 equiv) in an organicsolvent (such as 1,4-dioxane, NMP or DMF, preferably DMF) is addedpotassium cyanide (1-4 equiv, preferably 2.5 equiv), copper(I) iodide(1-4 equiv, preferably 2.5 equiv), tetrakis(triphenylphosphine)palladium(0) (0.01-0.05 equiv, preferably 0.01 equiv) and 18-crown-6(0.01-1.0 equiv, preferably 0.06-0.07 equiv). The reaction is heated atabout 25-120° C. (preferably about 110° C.) for about 0.5-10 h(preferably about 4 h). The reaction is cooled to rt and the organicsolvent is optionally removed under reduced pressure. The crude materialcan be partitioned between an organic solvent (such as EtOAc or DCM) andwater, an aqueous base (such as saturated aqueous NaHCO₃) or brine. Thelayers are separated and the aqueous layer is optionally washed with anorganic solvent (such as EtOAc or DCM). The combined organic extractsare dried over anhydrous Na₂SO₄ or MgSO₄, filtered, and concd underreduced pressure.

Illustration of General Procedure HHH Preparation #HHH.1*N-((1S,3S,4R)-3-(8-cyano-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-4-ethylcyclopentyl)cyclopropanesulfonamide

To a solution ofN-((1S,3R,4S)-3-ethyl-4-(8-iodo-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide(0.1 g, 0.16 mmol, prepared using KK from Preparation #GGG.1) in DMF(1.2 mL) was added potassium cyanide (0.03 g, 0.40 mmol), copper(I)iodide (0.076 g, 0.40 mmol), tetrakis(triphenyl-phosphine)palladium(0)(0.002 g, 0.002 mmol) and 18-crown-6 (0.003 g, 0.01 mmol). The reactionmixture was stirred at about 110° C. for about 4 h and cooled to ambienttemperature. The solvent was removed under reduced pressure. The residuewas partitioned between EtOAc (15 mL) and water (8 mL). The aqueouslayer was further extracted with EtOAc (15 mL). The combined organiclayers were dried with MgSO₄, filtered, and concd under reduced pressureto giveN-((1S,3S,4R)-3-(8-cyano-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-4-ethylcyclopentyl)cyclopropanesulfonamide(0.069 g, 82%): LC/MS (Table 1, Method b) R_(t)=2.50 min; MS m/z: 530(M+H)⁺.

General Procedure III: Horner-Wadsworth-Emmons Reaction of a Ketone

To a flask charged with a base (preferably NaH) (1-5 equiv, preferably1.2 equiv) in an organic solvent (preferably THF) at about 0-50° C.(preferably rt) is added a beta-ketophosphonate (1-5 equiv, preferably1.25 equiv). After the evolution of hydrogen gas has ceased a solutionof a ketone (preferably 1 equiv) in an organic solvent (preferably THF)is added. After about 1-20 h (preferably about 4 h) the reaction mixtureis partitioned between an organic solvent (such as DCM or EtOAc,preferably EtOAc) and an aqueous phase such as saturated aqueous NaHCO₃.The organic layer is separated and optionally washed with brine, driedover anhydrous Na₂SO₄ or MgSO₄, filtered, and concd under reducedpressure.

Illustration of General Procedure III Preparation #III.1 (E)-ethyl2-((3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylidene)acetate

To a slurry of NaH (0.034 g, 0.85 mmol) in THF (5 mL) was added ethyl2-(diethoxyphosphoryl)acetate (0.177 mL, 0.886 mmol) at rt. After about30 min, a solution of(3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanone(0.300 g, 0.708 mmol, Preparation #25) in THF (1 mL) was added. Afterabout 4 h, EtOAc (20 mL) and saturated aqueous NaHCO₃ (20 mL) wereadded. The organic layer was separated, concd in vacuo, and purified bychromatography on silica gel (40 g) eluting with EtOAc/heptane/DCM(2:1:1) to provide (E)-ethyl2-((3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylidene)acetate(0.260 g, 74%). LC/MS (Table 1, Method a) R_(t)=2.54 min; MS m/z: 494(M+H)⁺.

General Procedure JJJ: Formation of a Potassium Sulfonate

To a solution of a sulfonate (preferably 1 equiv) in an organic solvent(preferably 1,4-dioxane) and water is added potassium thiocyanate (1-3equiv, preferably 1 equiv). The reaction is heated at about 80-100° C.(preferably about 100° C.) for about 5-24 h (preferably about 16 h). Thereaction mixture is cooled to ambient temperature and is concd underreduced pressure.

Illustration of General Procedure JJJ Preparation #JJJ.1 potassium1-ethylcyclopropane-1-sulfonate

To a solution of butyl 1-ethylcyclopropane-1-sulfonate (0.46 g, 2.23mmol prepared from Preparation #6 Step A and ethyl iodide using KKK) in1,4-dioxane (2.79 mL) and water (2.79 mL) was added potassiumthiocyanate (0.12 mL, 2.23 mmol). The reaction is heated to about 100°C. for about 16 h. The reaction mixture was cooled to ambienttemperature and was concd under reduced pressure to afford potassium1-ethylcyclopropane-1-sulfonate (0.42 g, 100%) as a white crystallinesolid: ¹H NMR (400 MHz, DMSO) d 1.70-1.58 (m, 2H), 0.89 (t, J=7.5, 3H),0.80 (q, J=3.8, 2H), 0.32 (q, J=3.8, 2H).

General Procedure KKK: Alkylation of a Sulfonate

To a solution of a sulfonate (preferably 1 equiv) in an organic solvent(preferably THF), cooled to about −78-0° C. (preferably −78° C.) isadded an organic base such as n-BuLi, KHMDS, or LDA (preferably n-BuLi)(1-3 equiv, preferably 1 equiv) and an alkylating reagent such asiodomethane, iodoethane, or trifluoroethyl iodide (1-5 equiv, preferably1.2 equiv). The reaction is stirred at about −78-25° C. (preferably −78°C.) for about 1-24 h (preferably 2 h). Optionally, the reaction iswarmed to ambient temperature and stirred for about 1-24 h (preferably 2h). The reaction mixture is quenched by the addition of saturatedaqueous ammonium chloride. The reaction mixture is partitioned betweenan organic solvent (such as DCM or EtOAc) and water or brine. The layersare separated and the organic layer is optionally washed with waterand/or brine, dried over anhydrous Na₂SO₄ or MgSO₄, filtered, and concdunder reduced pressure.

Illustration of General Procedure KKK Preparation #KKK.1 butyl1-methylcyclopropane-1-sulfonate

To a solution of butyl cyclopropanesulfonate (1.5 g, 8.4 mmol,Preparation #6 Step A) in THF (8 mL) at about −78° C. was added n-BuLi(1.6 M in hexanes, 5.26 mL, 8.42 mmol) and iodomethane (0.684 mL, 10.9mmol) simultaneously. The resulting mixture was stirred at about −78° C.for about 2 h and then at ambient temperature for about 2 h. Thereaction was quenched by the addition of saturated aqueous NH₄Cl (7 mL)and the layers were separated. The aqueous layer was extracted withEtOAc (15 mL) and the combined organic extracts were dried overanhydrous MgSO₄, filtered, and concd under reduced pressure. The residuewas purified by silica gel column chromatography eluting with 5 to 25%EtOAc in heptanes to yield butyl 1-methylcyclopropane-1-sulfonate (0.8g, 49%) as a colorless oil. ¹H NMR (DMSO-d₆) δ 4.17 (t, 2H), 1.62 (m,2H), 1.43 (s, 3H), 1.35 (m, 2H), 1.22 (m, 2H), 0.94 (m, 2H), 0.88 (t,3H).

General Procedure LLL: Oxidation of a Thioether to a Sulfone

To a solution of a thioether (preferably 1 equiv) in an organic solvent(preferably DCM) is added an oxidant (such as m-CPBA, ozone, preferablym-CPBA) (1-4 equiv, preferably 2 equiv). The reaction is stirred atambient temperature for about 0.25-24 h (preferably about 0.5 h). Thereaction mixture is optionally filtered, washed with additional DCM, andthe filtrate is concd under reduced pressure. The reaction mixture isoptionally quenched with the addition of an aqueous base (such assaturated aqueous NaHCO₃) and partitioned between an organic solvent(such as DCM or EtOAc, preferably DCM). The layers are separated andoptionally washed with water and/or brine, dried over anhydrous Na₂SO₄or MgSO₄, filtered, and concd under reduced pressure to give a sulfone.

Illustration of General Procedure LLL Preparation #LLL.11-(2-ethyl-4-(2,2,2-trifluoroethylsulfonyl)cyclopentyl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine

To a mixture of1-(2-ethyl-4-(2,2,2-trifluoroethylthio)cyclopentyl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine(0.100 g, 0.200 mmol, Preparation #MMM.1) in DCM (0.667 mL) was addedm-CPBA (0.090 g, 0.400 mmol). The reaction stirred at ambienttemperature for about 0.5 h. The reaction mixture was quenched by theaddition of saturated aqueous NaHCO₃ (5 mL). The aqueous portion wasextracted with DCM (2×10 mL). The combined organic layers wereseparated, dried over anhydrous MgSO₄, filtered, and concd under reducedpressure. The crude material was purified by silica gel chromatographyeluting with a gradient of 0-60% EtOAc in DCM to afford1-2-ethyl-4-(2,2,2-trifluoroethylsulfonyl)cyclopentyl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine(0.095 g, 89%, 93% purity) as a clear oil: LC/MS (Table 1, Method a)R_(t)=2.63 min; MS m/z: 532 (M+H)⁺.

General Procedure MMM: Mitsunobu Reaction Using a Thiol

To a solution of an azodicarboxylate such as DIAD, DEAD, or TMAD(preferably DIAD) (1-2 equiv, preferably 1.2 equiv) in an organicsolvent (preferably THF) is added a phosphine reagent such as PPh₃ orP(n-Bu)₃ (preferably P(n-Bu)₃) (1-2 equiv, preferably 1.2 equiv), analcohol (preferably 1 equiv), TEA (1-2 equiv, preferably 1.2 equiv) anda thiol (1-1.5 equiv, preferably 1.2 equiv). The reaction is stirred atambient temperature for about 1-24 h (preferably 16 h). The reactionmixture is optionally concd under reduced pressure to give a residue.The reaction mixture or residue is partitioned between an organicsolvent (such as DCM or EtOAc, preferably EtOAc) and water, an aqueousbase (such as saturated aqueous NaHCO₃) or brine. The layers areseparated and the organic layer is optionally washed with water, anaqueous base (such as saturated aqueous NaHCO₃) and/or brine, dried overanhydrous Na₂SO₄ or MgSO₄, filtered, and concd under reduced pressure togive a thioether.

Illustration of General Procedure MMM Preparation #MMM.11-(2-ethyl-4-(2,2,2-trifluoroethylthio)cyclopentyl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine

An oven-dried flask was charged with DIAD (0.177 mL, 0.896 mmol) and THF(3.74 mL). The reaction flask was cooled to 0° C. before the addition ofP(n-Bu)₃ (0.221 mL, 0.896 mmol),3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanol(0.300 g, 0.747 mmol, prepared from Preparation #20 using KK and SS),TEA (0.125 mL, 0.896 mmol) and 2,2,2-trifluoroethanthiol (0.080 mL,0.896 mmol). The reaction was stirred at ambient temperature for about16 h. The reaction mixture was partitioned between water (10 mL) andEtOAc (10 mL). The aqueous layer was extracted with EtOAc (3×10 mL). Thecombined organic layers were dried over anhydrous MgSO₄, filtered, andconcd under reduced pressure to afford a crude oil. The crude materialwas purified by silica gel chromatography eluting with a gradient of0-60% EtOAc in DCM to afford1-(2-ethyl-4-(2,2,2-trifluoroethylthio)cyclopentyl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine(0.165 g, 44%) as an orange solid: LC/MS (Table 1, Method a) R_(t)=3.02min; MS m/z: 500 (M+H)⁺.

General Procedure NNN: Curtius Rearrangement to Form an Isocyanate

To a solution of a carboxylic acid (preferably 1 equiv) in an organicsolvent such as t-BuOH or toluene (preferably t-BuOH) is added DPPA (1-3equiv, preferably 1-1.1 equiv) and an organic base such as TEA (2-4equiv, 2.2 equiv). The reaction is stirred at about 25-110° C.(preferably about 70° C. for t-BuOH and 110° C. for toluene) for about0.5-16 h (preferably about 2 h). The reaction mixture is cooled toambient temperature and is optionally concd under reduced pressure togive a residue. The reaction mixture or residue is optionallypartitioned between an organic solvent (such as DCM or EtOAc) and water,an aqueous base (such as saturated aqueous NaHCO₃) or brine. The layersare separated and the organic layer is dried over anhydrous Na₂SO₄ orMgSO₄, filtered, and concd under reduced pressure.

Illustration of General Procedure NNN Preparation #NNN.1N-(3-isocyanato-4-methylcyclopentyl)cyclopropanesulfonamide

To a solution of4-(cyclopropanesulfonamido)-2-methylcyclopentanecarboxylic acid (4.10 g,16.58 mmol, prepared from Example #24 Step I using Y, K, and Z) and DPPA(3.58 mL, 16.58 mmol) in t-BuOH (55 mL) was added TEA (5.0 mL, 36.5mmol). The reaction was heated to about 70° C. for about 2 h then cooledto ambient temperature and concd under reduced pressure to afford acrude residue. The crude material was purified by silica gelchromatography eluting with a gradient of 0-10% MeOH in DCM to affordN-(3-isocyanato-4-methylcyclopentyl)cyclopropanesulfonamide (3.25 g,80%) as a white solid: LC/MS (Table 1, Method n) R_(t)=0.49 min; MS m/z:245 (M+H)⁺.

General Procedure OOO: Hydrolysis of an Isocyanate

To a mixture of an isocyanate (preferably 1 equiv) in an organic solvent(preferably THF) is added an aqueous base or acid (such as aqueous NaOH,LiOH, or HCl) (10-50 equiv, preferably 20 equiv). The reaction is heatedat about 30-100° C. for about 5-36 h (preferably about 50° C. for about16 h). The reaction is cooled to ambient temperature and the reactionmixture is partitioned between an organic solvent (such as DCM or EtOAc)and water, an aqueous base (such as saturated aqueous NaHCO₃) or brine.The layers are separated and the organic layer is optionally washed withwater and or brine, dried over anhydrous Na₂SO₄ or MgSO₄, filtered, andconcd under reduced pressure.

Illustration of General Procedure OOO Preparation #OOO.1N-(3-amino-4-methylcyclopentyl)cyclopropanesulfonamide

To a mixture ofN-(3-isocyanato-4-methylcyclopentyl)cyclopropanesulfonamide (1.00 g,4.09 mmol, Preparation #NNN.1) in THF (2.0 mL) was added aqueous LiOH (4N, 20.5 mL, 82 mmol). The reaction was heated to about 50° C. for about16 h, cooled to ambient temperature and partitioned between water (5 mL)and EtOAc (10 mL). The organic portion was separated and the aqueousportion was extracted with DCM (3×20 mL). The combined organic extractswere dried over anhydrous MgSO₄, filtered, and concd under reducedpressure to give crudeN-(3-amino-4-methylcyclopentyl)cyclopropanesulfonamide (0.66 g, 74%) asa white solid: LC/MS (Table 1, Method n) R_(t)=0.020 min; MS m/z: 219(M+H)⁺.

General Procedure PPP: Formation of an Oxime Ether from a Ketone

To a solution of a ketone (preferably 1 equiv) in an organic solvent(preferably EtOH) is added an O-alkyl hydroxylamine (1-10 equiv,preferably about 1 equiv). If the O-alkyl hydroxylamine is ahydrochloride salt, an organic base is added such as TEA or DIEA(preferably TEA, 1-5 equiv, preferably about 1.5 equiv). The reactionmixture is stirred at ambient temperature for about 12-24 h (preferablyabout 18 h). In cases where the reaction does not proceed to completionas monitored by TLC, LC/MS, or HPLC, additional O-alkyl hydroxylaminemay be added (1-10 equiv, preferably about 1 equiv). The reaction isstirred at ambient temperature for about 1-24 h (preferably about 5 h).The solvent is removed under reduced pressure.

Illustration of General Procedure PPP Example #PPP.1.1(3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanoneO-cyclopropylmethyl oxime

To a solution of(3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanone(0.05 g, 0.19 mmol, Example #AA.1.59) in EtOH (1 mL) was added TEA (0.04mL, 0.28 mmol) and O-(cyclopropylmethyl)hydroxylamine hydrochloride(0.02 g, 0.19 mmol, Huhu Technologies). The reaction mixture was stirredfor about 18 h at ambient temperature. AdditionalO-(cyclopropylmethyl)hydroxylamine hydrochloride (0.02 g, 0.19 mmol,Huhu Technologies) was added. The reaction was stirred at ambienttemperature for about 5 h. The solvent was removed under reducedpressure. The crude material was purified by silica gel chromatographyeluting with a gradient of 1-10% MeOH in DCM to afford(3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanoneO-cyclopropylmethyl oxime (0.051 g, 80%): LC/MS (Table 1, Method a)R_(t)=1.94 min; MS m/z: 339 (M+H)⁺.

TABLE PPP.1 Examples prepared using PPP and(3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanone (Example #AA.1.59)R_(t) min (Table 1 m/z ESI+ Hydroxylamine Structure Ex. # method) (M +H)⁺ O-(2-(methylsulfonyl)ethyl) hydroxylamine (Huhu Technologies)

PPP.1.2 1.63 (a) 391 O- (cyclobutylmethyl)hydroxylamine (HuhuTechnologies)

PPP.1.3 2.15-2.12 (a) 353 O-(tetrahydro-2H-pyran-4- yl)hydroxylamine(Huhu Technologies)

PPP.1.4 1.72 (a) 369General Procedure QQQ: Acid-Mediated Conversion of a t-Butyl Ester to aCarboxylic Acid with TFA

To a t-butyl ester (preferably 1 equiv) is added TFA (10-400 equiv,preferably 200-250 equiv). The reaction is maintained at about −20-60°C. (preferably about 25° C.) for about 0.5-16 h (preferably about 1 h).In any case where an additional acid labile group is present (forexample, a Boc group) this group may also be cleaved during thereaction. The reaction mixture is concd under reduced pressure. Theresulting residue can be used without further purification or dissolvedin an organic solvent such as DCM or EtOAc (preferably DCM) and iswashed with an aqueous inorganic base such as NaHCO₃ or Na₂CO₃(preferably saturated aqueous NaHCO₃). The organic layer is optionallywashed with brine, dried over anhydrous MgSO₄ or Na₂SO₄, and concd underreduced pressure to yield the target compound.

Illustration of General Procedure QQQ Preparation #QQQ.14-(cyclopropanesulfonamidomethyl)-2-ethylcyclopentanecarboxylic acid

tert-Butyl4-(cyclopropanesulfonamidomethyl)-2-ethylcyclopentanecarboxylate (0.080g, 0.241 mmol, prepared using K from Preparation #21 andcyclopropylsulfonyl chloride) in TFA (4 mL, 51.9 mmol) was stirred atabout 25° C. for about 1 h. The organic solvent was removed underreduced pressure to yield crude4-(cyclopropanesulfonamidomethyl)-2-ethylcyclopentanecarboxylic acid(0.066 g, 100%): LC/MS (Table 1, Method b) R_(t)=1.81 min; MS m/z: 276(M+H)⁺.

General Procedure RRR: Reduction of an Alkyne to an Alkene

To a flask charged with a hydrogenation catalyst (preferably Lindlarcatalyst) (0.001 to 1 equiv, preferably 0.01 equiv) is added a solvent(preferably THF) and an additive to prevent over-reduction (such aspyridine or quinoline, preferably pyridine) in a ratio of 5:1 to 20:1(preferably 10:1) followed by an alkyne (1 equiv). The reaction mixtureis sparged with hydrogen for about 5-30 min (preferably about 10 min)and an atmosphere of hydrogen is maintained via balloon. After about1-40 h (preferably about 15 h) the reaction mixture is filtered, dilutedwith an organic solvent (preferably Et₂O) and washed with saturatedaqueous CuSO₄, followed by water. The organic layer is separated, driedover anhydrous Na₂SO₄ or MgSO₄, filtered, and concd under reducedpressure.

Illustration of General Procedure RRR Preparation #RRR.1 (Z)-ethylpent-2-enoate

To a slurry of Lindlar catalyst (0.844 g, 0.396 mmol) in THF (100 mL)and pyridine (10.00 mL) was added ethyl pent-2-ynoate (5.22 mL, 39.6mmol). The reaction mixture was sparged with hydrogen for about 10 minand an atmosphere of hydrogen was maintained via balloon. After about 15h the reaction mixture was filtered through a pad of Celite®, dilutedwith Et₂O (30 mL) and washed with saturated aqueous CuSO₄ (40 mL),followed by water (40 mL). The organic layer was separated, dried overanhydrous MgSO₄, filtered, and concd in vacuo to provide crude (Z)-ethylpent-2-enoate (5 g, 98%). ¹H NMR (DMSO-d₆) δ 1.05 (t, 3H), 1.28 (t, 3H),2.65 (m, 2H), 4.18 (q, 2H), 5.72 (m, 1H), 6.21 (m, 1H).

General Procedure SSS: 1,3-Dipolar Cycloaddition to Form a Pyrrolidine

To a solution of a 1,3-dipole precursor (0.5-3 equiv, preferably 1equiv) and a dipolarophile (0.5-3 equiv, preferably 1 equiv) in anorganic solvent (preferably DCM) at about 0-45° C. (preferably rt) isadded an acid (preferably TFA) (0.001-1 equiv, preferably 0.01 equiv).After about 1-60 h (preferably about 48 h) the mixture is concd in vacuoto provide the crude cyclo-adduct.

Illustration of General Procedure SSS Preparation #SSS.1 cis-ethyl1-benzyl-4-ethylpyrrolidine-3-carboxylate

To a solution ofN-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (9.98 mL, 39.0mmol,) and (Z)-ethyl pent-2-enoate (5 g, 39.0 mmol, Preparation #RRR.1)in DCM (50 mL) was added TFA (0.030 mL, 0.390 mmol) at rt. After about 2d, the reaction mixture was concd in vacuo to provide crude cis-ethyl1-benzyl-4-ethylpyrrolidine-3-carboxylate (9.8 g, 96%) as an oil. LC/MS(Table 1, Method a) R_(t)=0.51 min; MS m/z: 262 (M+H)⁺.

General Procedure TTT: Hydrogenation of an Azide to an Amine

To an azide (preferably 1 equiv) in EtOH, MeOH, EtOAc or THF (preferablyEtOH), a catalyst such as 20 wt % palladium hydroxide on carbon or 10%wt palladium on carbon (preferably palladium hydroxide on carbon,0.05-0.5 eq., preferably 0.15 equiv) is added and the mixture is stirredat ambient temperature under atmospheric pressure of hydrogen for 1-24h, preferably about 2 h. The catalyst is removed by filtration through apad of Celite® and the filtrate is concd under reduced pressure to yieldthe desired product.

Illustration of General Procedure TTT Preparation #TTT.1(3S,5R)-5-ethyl-1-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)pyrrolidin-3-amine

To the solution of8-((2R,4S)-4-azido-2-ethylpyrrolidin-1-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine(0.136 g, 0.459 mmol, prepared using S from Example #3 Step E andtert-butyl bromoacetate, E with HCl, H with(2R,4S)-4-azido-2-methylpyrrolidine (prepared from (2R,4S)-tert-butyl4-azido-2-methylpyrrolidine-1-carboxylate as detailed in Rosen, T.; Chu,D. T. W.; Lico, I. M.; Fernandes, P. B.; Marsh, K.; Shen, L.; Cepa, V.G.; Pernet, A. G. J. Med. Chem. 1988, 31, 1598-1611, then E with HCl),OO, D with NaOH) in EtOH (15 mL), 20% palladium hydroxide on carbon(0.05 g, 0.071 mmol) was added and the reaction mixture was stirredunder atmospheric pressure of hydrogen for 2 h. The catalyst was removedby filtration through a pad of Celite® and the solvent was removed underreduced pressure to yield(3S,5R)-5-ethyl-1-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)pyrrolidin-3-amine(0.11 g, 89%) as an off-white amorphous solid. LC/MS (Table 1, Method a)R_(t)=1.00 min; MS m/z 271 (M+H)⁺.

General Procedure UUU: Reaction of an Aryl or Heteroaryl Halide with aBoronic Acid or Boronate Ester Followed by Tosyl Deprotection

To a mixture of an aryl halide (preferably 1 equiv), a boronic acid orboronate ester (1-1.75 equiv, preferably 1.1 equiv), and an inorganicbase (for example, potassium fluoride, sodium carbonate or cesiumcarbonate, preferably cesium carbonate (2-16 equiv, preferably 2.5equiv) in a solvent (for example THF, DME, DMF, 1,4-dioxane, DME/water,1,4-dioxane/water, toluene/EtOH/water, 1,4-dioxane/EtOH/water, water;preferably 1,4-dioxane/EtOH/water) is added a palladium catalyst (forexample tris(benzylideneacetone)dipalladium(0),tetrakis(triphenylphosphine)palladium(0),bis(acetato)triphenylphosphinepalladium(II), polymer-bound FibreCat™1032, (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II)complex with DCM, or dichlorobis(triphenylphosphine)palladium(II);preferably dichlorobis(triphenylphosphine)palladium(II) (0.01-0.20equiv, preferably 0.1 equiv)). The reaction mixture is heated at about40-120° C. (preferably about 60° C.) for about 1-24 h (preferably about6 h) thermally, or at about 100-200° C. (preferably about 120° C. forabout 5-60 min (preferably about 20 min) in a microwave (preferably 5min ramp time, 300 Watts max power, 250 psi max pressure). The reactionmixture is allowed to cool to ambient temperature and is worked up usingone of the following methods. Method 1. For reactions containing water,the reaction mixture may be diluted with an organic solvent (such as DCMor EtOAc). The layers are separated, the organic solution is optionallywashed with water and/or brine, dried over anhydrous MgSO₄ or Na₂SO₄,filtered, and the solvent is removed under reduced pressure to give theintermediate. Method 2. The reaction mixture is concd under reducedpressure and optionally purified using one or more of the PurificationMethods described above to give the intermediate. To the intermediateare added an organic solvent (such as 1,4-dioxane, MeOH, or THF/MeOH,preferably 1,4-dioxane) and an aqueous base (such as aqueous Na₂CO₃ oraqueous NaOH, 1-30 equiv, preferably 2-3 equiv for aqueous NaOH,preferably 15-20 equiv for aqueous Na₂CO₃). The mixture is stirred atabout 25-100° C. (preferably about 60° C.) for about 1-72 h (preferablyabout 1-16 h) thermally or at about 80-200° C. (preferably about 100°C.) for about 10-60 min (preferably about 15 m) in a microwave(preferably 5 min ramp time, 300 Watts max power, 250 psi max pressure).In cases where the reaction does not proceed to completion as monitoredby TLC, LC/MS, or HPLC, additional aqueous base (such as aqueous Na₂CO₃,10-20 equiv, preferably 10 equiv or aqueous NaOH, 1-5 equiv, preferably1-2 equiv) and/or a cosolvent (such as EtOH) are added. The reaction iscontinued at about 25-100° C. (preferably about 60° C.) for about 0.25-3h (preferably about 1-2 h) thermally or at about 80-100° C. (preferablyabout 100° C.) for about 10-60 min (preferably about 15 min) in amicrowave. In any case where an additional base labile group is present(for example, an ester or a cyano group), this group may also behydrolyzed. The reaction is worked up using one of the followingmethods. Method 1. The organic solvent is optionally removed underreduced pressure and the aqueous solution is neutralized with theaddition of a suitable aqueous acid (such as aqueous HCl). A suitableorganic solvent (such as EtOAc or DCM) and water are added, the layersare separated, and the organic solution is dried over anhydrous Na₂SO₄or MgSO₄, filtered, and concd to dryness under reduced pressure to givethe target compound. Method 2. The organic solvent is optionally removedunder reduced pressure, a suitable organic solvent (such as EtOAc orDCM) and water are added, the layers are separated, and the organicsolution is dried over anhydrous Na₂SO₄ or MgSO₄, filtered, and concd todryness under reduced pressure to give the target compound. Method 3.The reaction mixture is concd under reduced pressure and directlypurified by one of the subsequent methods to give the target compound.

Illustration of General Procedure UUU Example #UUU.11-cyclohexyl-3-(4-(methylsulfonyl)phenyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine

A microwave vial was charged with3-bromo-1-cyclohexyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine(0.050 g, 0.11 mmol, Preparation #MM.1), 4-(methylsulfonyl)phenylboronicacid (0.023 g, 0.12 mmol, Acros), cesium carbonate (0.086 g, 0.26 mmol),dichlorobis(triphenylphosphine)palladium(II) (0.0066 g, 0.0000094 mmol),and 1,4-dioxane (0.42 mL), EtOH (0.42 mL), and water (0.21 mL). The vialwas capped and the mixture was heated to about 120° C. for about 20 min(5 min ramp time, 300 Watts max power, 250 psi max pressure) in amicrowave. The reaction mixture was concd under reduced pressure to givea solid that was dissolved in 1,4-dioxane (1.0 mL) and transferred to amicrowave vial. Aqueous 2 N NaOH (0.11 mL, 0.21 mmol) was added and thevial was capped. The solution was heated to about 100° C. for about 15min in a microwave (300 W max power, 250 psi max pressure, 5 min ramptime). DCM (10 mL) and saturated aqueous NH₄Cl (5 mL) were added to thereaction solution. The layers were separated and the aqueous solutionwas extracted with additional DCM (5 mL). The combined extracts weredried over anhydrous MgSO₄, filtered, and concentrated to dryness underreduced pressure to give a light brown solid. Upon addition of DCM (1mL), a yellow precipitate formed that was collected by vacuum filtrationand dried overnight on a Buchner funnel to give1-cyclohexyl-3-(4-(methylsulfonyl)phenyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine(0.017 g, 41%): LC/MS (Table 1, Method a) R_(t)=2.39 min; MS m/z: 395(M+H)⁺.

TABLE UUU.1 Examples prepared from3-bromo-1-cyclohexyl-6-tosyl-6H-imidazo[1,5- a]pyrrolo[2,3-e]pyrazine(Preparation #MM.1) using General Procedure UUU R_(t) min (Table 1, m/zESI+ Boronic acid or boronate ester Product Example # Method) (M + H)⁺N-(4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)methanesulfonamide

UUU.1.1 2.25 (a) 410General Procedure VVV: Reaction of an Aryl or Heteroaryl Halide with aBoronic Acid or Boronate Ester

To a mixture of an aryl halide (preferably 1 equiv), a boronic acid orboronate ester (1-1.75 equiv, preferably 1.1 equiv), and an inorganicbase (for example, potassium fluoride, sodium carbonate or cesiumcarbonate, preferably cesium carbonate) (1.1-16 equiv, preferably 2equiv) in a solvent (for example THF, DME, DMF, 1,4-dioxane, DME/water,1,4-dioxane/water, toluene/EtOH/water, 1,4-dioxane/EtOH/water or water;preferably 1,4-dioxane) is added a palladium catalyst (for exampletris(benzylideneacetone)dipalladium(0),tetrakis(triphenylphosphine)palladium(0),bis(acetato)triphenylphosphinepalladium(II), polymer-bound FibreCat™1032, (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II)complex with DCM, or dichlorobis(triphenylphosphine)palladium(II);preferably tris(benzylideneacetone)dipalladium(0), 0.01-0.20 equiv,preferably 0.1 equiv) and a ligand (for example tricyclohexylphosphine,tri-t-butyl-phosphane; preferably tricyclohexylphosphine (0.01-1.0equiv, preferably 0.16 equiv)) is added optionally. The reaction mixtureis heated at about 40-120° C. (preferably about 85° C.) for about 1-24 h(preferably about 2 h) thermally, or at about 100-200° C. (preferablyabout 120° C.) for about 5-60 min (preferably about 20 min) in amicrowave (preferably 5 min ramp time, 300 Watts max power, 250 psi maxpressure). The reaction mixture is allowed to cool to ambienttemperature and is worked up using one of the following methods.Method 1. For reactions containing water, the reaction mixture may bediluted with an organic solvent (such as DCM or EtOAc). The layers areseparated, the organic solution is optionally washed with water and/orbrine, dried over anhydrous MgSO₄ or Na₂SO₄, filtered, and the solventis removed under reduced pressure to give the desired compound. Method2. The reaction mixture is concd under reduced pressure and optionallypurified using one or more of the Purification Methods described aboveto give the desired compound. Method 3. The catalyst is removed byfiltration and the filtrate is concentrated under reduced pressure.

Illustration of General Procedure VVV Preparation #VVV.18-cyclohexyl-1-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine

To the solution of8-cyclohexyl-1-iodo-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine(0.100 g, 0.201 mmol, prepared using GGG with8-cyclohexyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine [WO2009152133A1],KK) in 1,4-dioxane (1 mL) was added cesium carbonate (0.131 g, 0.403mmol), tricyclohexylphosphine (20 wt % solution in toluene, 0.045 g,0.032 mmol), Pd₂(dba)₃ (0.018 g, 0.020 mmol) and trimethylborate (0.033g, 0.262 mmol). The mixture was degassed and heated at about 85° C. forabout 2 h. The catalyst was filtered off. The filtrate was concentratedand purified by RP-HPLC (Table 1, Method s) to give8-cyclohexyl-1-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine(0.032 g, 41%) as a clear oil: LC/MS (Table 1, Method b) R_(t)=3.41 min;MS m/z: 385 (M+H)⁺.

General Procedure WWW: Formation of a Carbamate

To an amine (2-10 equiv, preferably 5 equiv) and DMAP (0-5 equiv,preferably 2 equiv) in an organic solvent (such as THF or 1,4-dioxane,preferably 1,4-dioxane) at about −20° C. to 80° C. (preferably about 40°C.) is added a carbonate or a solution of a carbonate (preferably 1equiv) in an organic solvent (such as THF or 1,4 dioxane, preferably1,4-dioxane). After about 1-16 h (preferably about 2 h), the reactionmixture is either concd under reduced pressure or optionally dilutedwith an organic solvent (such as Et₂O, EtOAc or DCM, preferably EtOAc),washed with water and an aqueous base (such as saturated aqueous Na₂CO₃or NaHCO₃ and brine, dried over anhydrous Na₂SO₄ or MgSO₄, filtered, andconcd under reduced pressure.

Illustration of General Procedure WWW Preparation #WWW.1(1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylphenylcarbamate

To aniline (0.063 g, 0.677 mmol) and DMAP (0.033 g, 0.271 mmol) in1,4-dioxane (1 mL) at about 40° C. was added a solution of(1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl4-nitrophenyl carbonate (0.080 g, 0.135 mmol, prepared from Example #42Step N) in 1,4-dioxane (1 mL). After about 2 h, the solvent was removedand the residue was purified by silica gel chromatography (12 g) elutingwith 0-40% EtOAc in DCM to give(1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylphenylcarbamate (0.0468 g, 63%): LC/MS (Table 1, Method b) R_(t)=2.58min; MS m/z: 545 (M+H)⁺.

General Procedure XXX: Urea Formation with Loss of Protecting Group

To a solution or slurry of an amine or amine salt (1-3 equiv, preferably1-2 equiv) in an organic solvent such as DCM, THF, or DMF (preferablyTHF) at about 20-80° C. (preferably about 20° C.) is optionally added anorganic base, such as TEA, DIEA, pyridine (preferably DIEA) (1-10 equiv,preferably 1-5 equiv) followed by CDI (1-5 equiv, preferably 1 equiv).After about 0.5-24 h (preferably about 1-3 h), a second amine or aminesalt (1-10 equiv, preferably 1-3 equiv) is added neat or as a solutionor slurry in an organic solvent such as DCM, THF, or DMF (preferablyTHF). The reaction is held at about 20-80° C. for about 2-24 h(preferably about 16 h). If the reaction is not complete, the reactionmay be heated at about 40-80° C. (preferably 55° C.). In addition,additional amine or amine salt (1-50 equiv, preferably 20 equiv), and/orDMAP (1-10 equiv, preferably 1 equiv) may be added. The reaction is heldat about 20-80° C. for about 24-96 h (preferably 72 h). This may berepeated if the reaction is not complete by TLC, LC/MS, or HPLC. Thereaction mixture is cooled to ambient temperature. The reaction mixtureis optionally partitioned between an organic solvent (such as EtOAc orDCM) and an aqueous base (such as saturated aqueous NaHCO₃ or saturatedaqueous Na₂CO₃, preferably saturated aqueous NaHCO₃). Alternatively, thereaction mixture is concd under reduced pressure and the residue ispartitioned as above. In either case, the aqueous layer is thenoptionally extracted with additional organic solvent such as EtOAc orDCM. The combined organic layers may optionally be washed with brine andconcd in vacuo or dried over anhydrous Na₂SO₄ or MgSO₄ and then decantedor filtered prior to concentrating under reduced pressure. Optionally,the reaction mixture is concd under reduced pressure and the residue isdirectly purified.

Illustration of General Procedure XXX Preparation #XXX.1(cis)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrrolidine-1-carboxamide

To a solution of1-((cis)-4-ethylpyrrolidin-3-yl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazinehydrochloride (0.075 g, 0.168 mmol, Example #36, step F) in THF (1.00mL) was added DIEA (0.150 mL, 0.861 mmol) and CDI (0.027 g, 0.168 mmol).After about 1 h, 4-aminomethyltetrahydropyran (0.020 g, 0.17 mmol,Acros) was added and the reaction mixture was stirred at ambienttemperature for about 16 h. The reaction mixture was heated at about 55°C. for about 24 h. DMAP (0.021 g, 0.168 mmol) was added and continuedstirring at about 55° C. for about 48 h. 4-aminomethyltetrahydropyran(0.400 g, 3.47 mmol, Acros) was added and continued stirring at about55° C. for about 24 h. The solvent was removed under reduced pressure.The crude material was purified by RP-HPLC (Table 1, Method m) to afford(cis)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrrolidine-1-carboxamide(0.007 g, 10%) as product: LC/MS (Table 1, Method a) R_(t)=1.32 min; MSm/z: 398 (M+H)⁺.

TABLE XXX.1 Urea formation with loss of protecting group (prepared fromExample #36, step F) using General Procedure XXX R_(t) min (Table 1, m/zESI+ Starting material amine Product Ex # Method) (M + H)⁺cyclopropylmethanamine

 

XXX.1 1.62 (a) 354

General Procedure YYY: Michael Addition

To a mixture of a nucleophile (such as an amine or an alcohol,preferably 1 equiv) and a Michael acceptor (0.5-30 equiv, preferably 2-5equiv) optionally in an organic solvent (such as DMF, EtOH or MeCN,preferably DMF) is optionally added an organic base (such as TEA, DIEA,or DBU, preferably DBU, 1-5 equiv, preferably 1-2 equiv). The reactionmixture is heated at about 20-120° C. (preferably about 80° C.) forabout 2-60 h (preferably about 12-16 h). Optionally additional Michaelacceptor (0.5-30 equiv, preferably 2-5 equiv) is added followed byoptional addition of an organic base (such as TEA, DIEA, or DBU,preferably DBU, 1-5 equiv, preferably 1-2 equiv) and the reactionmixture is heated at about 20-120° C. (preferably about 80° C.) forabout 2-60 h (preferably about 2-5 h). In cases where the reaction doesnot proceed to completion as monitored by TLC, LC/MS, or HPLC, thereaction mixture is resubjected to the previously described conditions.The reaction mixture is then cooled to ambient temperature. Optionally,DCM is added and the suspension is filtered. The reaction mixture or theoptional filtrate is concentrated under reduced pressure.

Illustration of General Procedure YYY Preparation #YYY.12-(3-((1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentylamino)oxetan-3-yl)acetonitrile

To a solution of(1S,3R,4S)-3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentanamine(0.605 g, 1.569 mmol, prepared using FFFFF from Preparation #33, GGGGGwith Preparation #E.1.1, MUCK with PFPAA, D with NaOH, KK, Y) in DMF (6mL) was added 2-(oxetan-3-ylidene)acetonitrile (0.298 g, 3.14 mmol, J.Med. Chem. 2010, 53(8), 3227) and the reaction mixture was heated atabout 80° C. for about 15 h. 2-(Oxetan-3-ylidene)acetonitrile (0.149 g,1.569 mmol) was added and the reaction mixture was heated at about 80°C. for about 3.5 h. The reaction mixture was cooled to ambienttemperature, concentrated in vacuo and the residue was purified bysilica gel chromatography eluting with 0% to 10% MeOH in DCM. A secondpurification by silica gel chromatography eluting with 50% to 100% EtOAcin heptane followed by 10% MeOH in DCM yielded2-(3-((1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentylamino)oxetan-3-yl)acetonitrile(0.262 g, 33%) as a sticky brown solid: LC/MS (Table 1, Method n)R_(t)=0.75 min; MS m/z 481 (M+H)⁺.

General Procedure ZZZ: Grignard or Alkyl Lithium Addition to aCarbonyl-Containing Compound

A solution of a carbonyl-containing compound (preferably 1 equiv) in anorganic solvent (such as THF, 1,4-dioxane, Et₂O, preferably THF) wascooled to about −78° C.-50° C. (preferably about 0° C.) followed by theoptional addition of an additive such as lithium chloride (1-10 equiv,preferably 4 equiv) in an organic solvent (such as THF or Et₂O,preferably THF). To the reaction solution is added a solution of aGrignard reagent or alkyl lithium in an organic solvent (such as THF orEt₂O, preferably Et₂O) and the resulting mixture is stirred at about−78° C.-50° C. for about 15 min-2 h (preferably about 0° C. for about 20min) and then is optionally warmed to ambient temperature and stirredfor about 2-16 h (preferably about 4 h). In cases where the reaction didnot proceed to completion, an additional portion or portions of asolution of a Grignard reagent or alkyl lithium in an organic solvent(such as THF or Et₂O, preferably Et₂O) was added to drive the reactionto completion. The reaction mixture is then optionally cooled to about−78° C.-0° C. (preferably about −78° C.) and is quenched with theaddition of a saturated aqueous solution of NH₄Cl. The mixture isoptionally stirred for about 5-30 min (preferably about 5 min) followedby the addition of an organic solvent (such as EtOAc or DCM). The layersare separated and the organic solution is dried over anhydrous MgSO₄,filtered, and concentrated under reduced pressure.

Illustration of General Procedure ZZZ Example #ZZZ.11-((1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-2-methylpropan-2-ol

To a solution of ethyl2-((1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)acetate(0.166 g, 0.486 mmol, Example #38, Step H) in THF (4 mL) at about 0° C.was added lithium chloride in THF (0.5 M, 3.9 mL) followed bymethylmagnesium bromide in Et₂O (3.0 M, 0.65 mL). After about 20 min thereaction mixture was allowed to warm to rt. After about 4 h the reactionmixture was cooled to about −78° C. and saturated aqueous NH₄Cl (about 5mL) was added. After about 5 min the reaction mixture was allowed towarm to rt and EtOAc (about 10 mL) was added. The layers were separatedand the organic solution was dried over anhydrous MgSO₄, filtered, andconcentrated under reduced pressure. The crude material was purified bysilica gel chromatography eluting with EtOAc/MeOH to provide1-((1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-2-methylpropan-2-ol(0.118 g, 74%) as a foam: LC/MS (Table 1, Method a) R_(t)=1.64 min; MSm/z 328 (M+H)⁺.

TABLE ZZZ.1 Examples prepared using General Procedure ZZZ withmethylmagnesium bromide R_(t) min (Table 1, m/z ESI+ Ester Product Ex #Method) (M + H)⁺ ethyl 2-((1S,3R,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][l,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)acetate(prepared from Preparation #BBBB.1*, using W.1, from Preparation#BBBB.1, AA, Table 2, method 3)

ZZZ.1.1* 1.63 (a) 328 ethyl 2-((1R,3R,4S)-3-ethyl-4-(3-(trifluoromethyl)-6H-imidazo[1,5- a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentyl)acetate (Example #BBBB.1.1*)

ZZZ.1.2* 2.33 (a) 395General Procedure AAAA: Deprotection of a Sulfonamide with DBU

To a flask containing a sulfonamide, for example, a sulfonyl-protectedpyrrole, (preferably 1 equiv) in an organic solvent (such as1,4-dioxane, MeOH, or THF/MeOH, MeCN, preferably MeCN) is added DBU(1-30 equiv, preferably 5-6 equiv). The mixture is stirred at about20-100° C. (preferably about rt) for about 1-72 h (preferably about 24h). In cases where the reaction does not proceed to completion asmonitored by TLC, LC/MS, or HPLC the reaction is heated at about 30-100°C. (preferably about 45° C.) for about 1-48 h (preferably about 12-24h). In cases where the reaction does not proceed to completion asmonitored by TLC, LC/MS, or HPLC, additional DBU (1-20 equiv, preferably1 equiv) is added. This may be repeated if the reaction is not completeby TLC, LC/MS, or HPLC. The reaction is cooled to rt and worked up usingone of the following methods. Method 1. The organic solvent isoptionally removed under reduced pressure, a suitable organic solvent(such as EtOAc or DCM) and water or brine are added, the layers areseparated, and the organic solution is dried over anhydrous Na₂SO₄ orMgSO₄, filtered, and concd to dryness under reduced pressure to give thetarget compound. Method 2. The reaction mixture is concd under reducedpressure and directly purified by one of the subsequent methods.

Illustration of General Procedure AAAA Preparation #AAAA.1 (E/Z)-ethyl2-((3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylidene)acetate

To a solution of (E/Z)-ethyl2-((3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylidene)acetate(2.00 g, 4.05 mmol, Preparation #III.1) in MeCN (20 mL) was added DBU(3.70 mL, 24.51 mmol). The reaction mixture was stirred at rt for about16 h. The reaction mixture was heated at about 45° C. for about 24 h.DBU (1.00 mL, 6.63 mmol) was added and continued heating at about 45° C.for about 24 h. Additional DBU (1.00 mL, 6.63 mmol) was added andcontinued heating at about 45° C. for about 24 h. The reaction mixturewas cooled to rt and the solvent was removed under reduced pressure. Thecrude material was purified via flash chromatography on silica geleluting with a gradient of 0-10% MeOH in DCM to afford (E/Z)-ethyl2-((3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylidene)acetate(0.70 g, 51%) as a brown foam: LC/MS (Table 1, Method b) R_(t)=1.90-1.95min; MS m/z: 340 (M+H)⁺.

General Procedure BBBB: Deprotection of a Sulfonamide with TBAF

To a solution of a sulfonamide (preferably 1 equiv) in an organicsolvent (preferably THF) at about −30 to 65° C. (preferably 0° C.) isadded TBAF (1-10 equiv, preferably 3 equiv). Additional TBAF (1-10equiv, preferably 3 equiv) can be added to drive the reaction tocompletion. Once the reaction has preceded to an acceptable level thereaction mixture is partitioned between an organic solvent (such as DCMor EtOAc, preferably EtOAc) and an aqueous phase (such as water orbrine). The organic layer is separated and optionally washed with brine,dried over anhydrous Na₂SO₄ or MgSO₄, and/or filtered prior toconcentrating under reduced pressure.

Illustration of General Procedure BBBB Preparation #BBBB.1* Ethyl2-((3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylidene)acetate

To a solution of ethyl2-((3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylidene)acetate(1.9 g, 3.85 mmol, Preparation #III.1) in THF (30 mL) at about 0° C. wasadded a solution of TBAF (11.55 mL, 11.55 mmol, 1M in THF). After about30 min additional TBAF (7.70 mL, 7.70 mmol, 1M in THF) was added. Afterabout 1 h EtOAc and brine were added to the reaction mixture. Theorganic layer was separated, concd in vacuo and purified bychromatography on silica gel eluting with EtOAc to provide ethyl2-((3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylidene)acetate(1.3 g, 100%) as a mixture of stereoisomers. LC/MS (Table 1, Method a)R_(t)=1.86 and 1.90 min.; MS m/z: 340 (M+H)⁺.

TABLE BBBB.1 Examples prepared using General Procedure BBBB R_(t) minExample (Table 1, m/z ESI+ Sulfonamide Product # Method) (M + H)⁺ ethyl2-((1R,3R,4S)-3- ethyl-4-(6-tosyl-3- (trifluoromethyl)-6H- imidazo[1,5-a]pyrrolo[2,3- e]pyrazin-1- yl)cyclopentyl)acetate (prepared using Hwith Preparation #32 Preparation #31 HATU, and DIEA, and OO)

BBBB.1.1 2.62 (a) 409 N-((1S,3R,4S)-3-ethyl- 4-(6-tosyl-3-(2,2,2-trifluoroethyl)-6H- imidazo[1,5- a]pyrrolo[2,3- e]pyrazin-1-yl)cyclopentyl) cyclopropane- sulfonamide (prepared using H withPreparation #30 and Preparation #Z.l, and OO)

BBBB.1.X 2.04 (a) 456General Procedure CCCC: Deprotection of a Sulfonamide with KCN

To a flask containing a sulfonamide, for example, a sulfonyl-protectedpyrrole, (preferably 1 equiv) in an organic solvent (such as1,4-dioxane, MeOH, or THF, preferably MeOH) is added KCN (1-3 equiv,preferably 2.2 equiv) as a solution in an organic solvent (such as1,4-dioxane, MeOH, or THF, preferably MeOH) or as a solid. The mixtureis stirred at ambient temperature for about 1-18 h (preferably about 16h). The organic solvent is optionally removed under reduced pressure anda suitable organic solvent (such as EtOAc or DCM) and water are added.The layers are separated and the organic solution is dried overanhydrous Na₂SO₄ or MgSO₄, filtered or decanted, and concd to drynessunder reduced pressure and directly purified by one of the subsequentmethods.

Illustration of General Procedure CCCC Preparation #CCCC.13-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylbenzoate

To a mixture of3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylbenzoate (5.00 g, 7.84 mmol, prepared using II from Example #4 Step Jwith benzoic acid and B) in MeOH (16 mL) was added a solution ofpotassium cyanide (0.74 mL, 17 mmol) in MeOH (16 mL). The reaction wasstirred at ambient temperature for about 16 h. The reaction mixture wasconcd under reduced pressure to afford a residue. The residue waspartitioned between water (20 mL) and DCM (20 mL). The layers wereseparated and the aqueous layer was extracted with DCM (3×10 mL). Theextract was then washed with saturated aqueous NaHCO₃, dried overanhydrous MgSO₄, filtered, and concd under reduced pressure to afford acrude oil. The crude material was purified by silica gel chromatographyeluting with a gradient of 0-10% MeOH in DCM to3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylbenzoate (2.30 g, 78%) as a solid. LC/MS (Table 1, Method a) R_(t)=2.08min; MS m/z: 376 (M+H)⁺.

TABLE CCCC.1 Examples prepared using General Procedure D with KCN R_(t)min m/z (Table 1, ESI+ Sulfonamide Product Ex # Method) (M + H)⁺N-((1S,3R,4S)-3-ethyl-4-(6-tosyl- 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentyl)-N-((5-methylisoxazol-3-yl)methyl)oxetan- 3-amine (prepared using X fromExample #8 Step M with oxetan-3- one [PharmaBlock], and X with 5-methylisoxazole-3-carbaldehyde)

CCCC.1.1* 1.57 (a) 422

General Procedure DDDD: Formation of an Oxadiazole

To a solution of a carboxylic ester (preferably 1 equiv) in an organicsolvent (such as DMF, NMP, THF, MeOH/toluene, p-Dioxane, or MeOH,preferably MeOH/toluene) is added a base (such as K₂CO₃ or Cs₂CO₃, 2-10equiv, preferably 2-4 equiv) and an acetimidamide (1-20 equiv,preferably 4-10 equiv). The reaction mixture is heated at about 100-160°C. (preferably about 130° C.) for about 15 min to 2 h (preferably about45 min) under microwave irradiation. In cases where the reaction doesnot proceed to completion as monitored by TLC, LC/MS, or HPLC,additional acetimidamide (1-20 equiv, preferably 3-10 equiv) and/or base(such as K₂CO₃ or Cs₂CO₃, 2-10 equiv, preferably 2-4 equiv) may beadded. The reaction mixture is heated at about 100-160° C. (preferablyabout 130-140° C.) for about 15 min to 2 h (preferably about 45 min)under microwave irradiation. The additional heating with or withoutaddition of acetimidamide and/or base is optionally repeated.Alternatively, a solution of an acetimidamide (1-20 equiv, preferably4-10 equiv) in an organic solvent (such as THF or p-dioxane, preferablyTHF) is added a base (such as NaH, 1-5 equiv, preferably 3 equiv). Afterabout 0.5-2 h (preferably about 0.5 h), a carboxylic ester (preferably 1equiv) is added. After about 0.25-3 h (preferably about 0.25 h), thereaction mixture is heated at about 40-120° C. (preferably about 70° C.)for about 1-48 h (preferably about 4 h). If the reaction is heated thereaction mixture is cooled to ambient temperature. The reaction isworked up using one of the following methods. Method 1. The organicsolvent is optionally removed under reduced pressure, a suitable organicsolvent (such as EtOAc or DCM) and water, brine or saturated NH₄Cl areadded, the layers are separated. The organic solution is washed withwater, brine or saturated NH₄Cl and the organic solution is dried overanhydrous Na₂SO₄ or MgSO₄, filtered, and concd to dryness under reducedpressure to give the target compound. Method 2. The reaction mixture isconcd under reduced pressure and directly purified.

Illustration of General Procedure DDDD Preparation #DDDD.1(5-(((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methyl)-1,2,4-oxadiazol-3-yl)methanol

To a solution of ethyl2-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)acetate(0.195 g, 0.571 mmol, Example #38, Step H) in toluene (1.00 mL) and MeOH(1.000 mL) were added (Z)—N′,2-dihydroxyacetimidamide (0.515 g, 5.71mmol, Tyger) and K₂CO₃ (0.195 g, 1.41 mmol). The reaction was heated ina CEM microwave at about 130° C. twice at about 45 min each (250 psimaximum pressure, 1 min ramp, 300 max watts).(Z)—N′,2-dihydroxyacetimidamide (0.200 g, 2.22 mmol, Tyger) was addedand the reaction mixture was heated in a CEM microwave at about 140° C.for about 45 min (250 psi maximum pressure, 1 min ramp, 300 max watts).(Z)—N′,2-dihydroxyacetimidamide (0.200 g, 2.22 mmol, Tyger) and K₂CO₃(0.100 g, 0.725 mmol) were added, and the reaction mixture was heated ina CEM microwave at about 140° C. for about 45 min (250 psi maximumpressure, 1 min ramp, 300 max watts). The solvent was removed underreduced pressure. The residue was dissolved with water (20 mL) and EtOAc(50 mL). The aqueous layer was extracted with EtOAc (5×50 mL). Thecombined organic layers were dried over anhydrous MgSO₄, filtered, andconcd to give a yellow residue. The crude material was purified viaflash chromatography on silica gel eluting with a gradient of 0-10% MeOHin EtOAc to afford(5-(((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methyl)-1,2,4-oxadiazol-3-yl)methanol(0.042 g, 20%) as a yellow solid: LC/MS (Table 1, Method a) R_(t)=1.67min; MS m/z: 368 (M+H)⁺.

TABLE DDDD.1 Examples prepared using General Procedure DDDD with(Z)-N′-hydroxy- methoxyacetimidamide R_(t) min (Table 1, m/z ESI+ EsterProduct Ex # Method) (M + H)⁺ ethyl 2-((1R,3R,4S)-3-ethyl-4-(6-tosyl-3-(trifluoromethyl)-6H- imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentyl)acetate (Example # BBBB.1.1*)

DDDD.1.1* 2.41 (a) 449

General Procedure EEEE: Formation of a Urea Using Phosgene

To a solution of phosgene (1-1.5 equiv, preferably 1.2 equiv, 20%solution in toluene) in an organic solution (such as DCM), under aninert atmosphere at about 0° C. is added solution or slurry of an amineor amine salt (preferably 1 equiv) in an organic solvent (such as DCM,THF, or 1,4-dioxane, preferably DCM) and an organic base (such as TEA,DIEA, pyridine, 1-10 equiv, preferably 5 equiv, preferably TEA). Afterabout 0.5-24 h (preferably about 40 min) at about 0° C., a second amineor amine salt (1-10 equiv, preferably 1-3 equiv) is added neat or as asolution or slurry in an organic solvent (such as DCM, THF, or DMF,preferably DCM) and an organic base (such as TEA, DIEA, pyridine, 1-10equiv, preferably 5 equiv, preferably TEA). The reaction mixture isstirred at about 0° C. for 0.5-24 h (preferably 45 min). An aqueous base(such as aqueous NH₄OH or saturated aqueous Na₂CO₃) is added with theoptional addition of an organic solvent such as EtOAc or DCM. Theaqueous layer is then optionally extracted with additional organicsolvent (such as EtOAc or DCM). The combined organic layers mayoptionally be washed with water or brine and concd in vacuo or driedover anhydrous Na₂SO₄ or MgSO₄ and then decanted or filtered prior toconcentrating under reduced pressure to give the target compound.

Illustration of General Procedure EEEE Preparation #EEEE.1(3,3-difluoroazetidin-1-yl)((cis)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)pyrrolidin-1-yl)methanone

To a solution of phosgene (0.400 mL, 0.761 mmol, 20% in toluene) in DCM(1.5 mL) under a balloon of N₂ at about 0° C. were added a solution of1-((cis)-4-ethylpyrrolidin-3-yl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine(0.250 g, 0.609 mmol, Example #36, step F) in DCM (5.0 mL) and TEA(0.430 mL, 3.08 mmol). After about 40 min, at about 0° C., a solution of3,3-difluoroazetidine hydrochloride (0.095 g, 0.731 mmol, Matrix) andTEA (0.430 mL, 3.08 mmol) in DCM (5.0 mL) were added dropwise andstirred at about 0° C. for about 45 min. Saturated aqueous sodiumbicarbonate (2 mL) was added and the layers were separated. The aqueouslayer was extracted with DCM (2×30 mL). The combined organic layers werewashed with water (25 mL), dried over anhydrous MgSO₄, filtered, andconcd to give a brown residue. The crude material was purified via flashchromatography on silica gel eluting with a gradient of 0-10% MeOH inDCM to afford(3,3-difluoroazetidin-1-yl)((cis)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)pyrrolidin-1-yl)methanone(0.208 g, 65%) as a brown residue: LC/MS (Table 1, Method a) R_(t)=2.17min; MS m/z: 530 (M+H)⁺.

General Procedure FFFF: Formation of an Amide from an Ester

To a pressure reactor charged with an ester (preferably 1 equiv) isadded a solution of ammonia in a protic solvent (such as ethanol,methanol or water, preferably methanol). The reactor is sealed and thetemperature is maintained at about ambient temperature to about 200° C.(preferably about 85° C.). After about 1 to 10 days (preferably about 2days) the reaction mixture is cooled to rt and the reaction mixture isconcd in vacuo to provide the crude amide.

Illustration of General Procedure FFFF Example #FFFF.14-(3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)butanamide

Ethyl4-(3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)butanoate(0.080 g, 0.217 mmol, prepared using III from Preparation #25 and(E)-ethyl 4-(diethoxyphosphoryl)but-2-enoate, W) and ammonia (7 N inMeOH, 6.2 mL, 43.3 mmol). The reaction vessel was sealed and heated toabout 85° C. After about 2 days the tube was cooled to rt and thereaction mixture was concd in vacuo to provide4-((3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)butanamide(0.074 g, 100%) as a solid which was used without further purification:LC/MS (Table 1, Method c) R_(t)=0.50 min.; MS m/z: 341 (M+H)⁺.

General Procedure GGGG: Formation of a Nitrile from a Primary Amide

To solution of a primary amide (preferably 1 equiv) in an organicsolvent (such as DCM, THF, DCE, preferably DCM) is added a dehydratingreagent (such as TFAA or SOCl₂, preferably TFAA) (1-20 equiv, preferably10 equiv). After about 1-20 h (preferably about 4 h) at 10 to 60° C.(preferably ambient temperature) the reaction mixture is concd in vacuo.

Illustration of General Procedure GGGG Example #GGGG.14-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)butanenitrileand4-((1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)butanenitrile

To a solution of4-(3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)butanamide(0.090 g, 0.264 mmol, Example #FFFF.1) in DCM (3 mL) was added TFAA(0.373 mL, 2.64 mmol). After about 4 h at ambient temperature thereaction mixture was concd in vacuo and purified by chiral preparativeHPLC (Table 2, Method 33) to provide4-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)butanenitrile(0.013 g, 15%) (rt=16.1 min, or =neg) LC/MS (Table 1, Method a)R_(t)=1.79 min; MS m/z: 323 (M+H)⁺ and4-((1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)butanenitrile(0.010 g, 12%) (rt=13.7 min, or =neg) LC/MS (Table 1, Method a)R_(t)=1.79 min; MS m/z: 323 (M+H)⁺ as solids.

General Procedure HHHH: O-alkylation with KOH or NaOH and TBAB

To an alcohol (preferably 1 equiv) is added an aqueous base (such as 50%w/v KOH or 50% w/v NaOH, 1-60 equiv, preferably 11-24 equiv) and asolvent (such as 1,4-dioxane or THF, preferably 1,4-dioxane) and thereaction mixture is heated to about 45-100° C. (preferably about 70°C.). To the reaction mixture is added an alkyl halide or mesylate (1-30equiv, preferably 8-16 equiv), and TBAB (0.05-2 equiv, preferably0.08-1.6 equiv) and stirred for about 8-48 h (preferably about 24 h).Alternatively, the order of addition may be reversed. In cases where thereaction does not proceed to completion as monitored by TLC, LC/MS, orHPLC, the reaction may be re-subjected to heating at about 25-100° C.(preferably about 70° C.) for about 2-48 h (preferably about 8-24 h)with the optional addition of more base (such as 50% w/w aqueous KOH or50% w/w aqueous NaOH, 1-60 equiv, preferably 11-24 equiv), solvent (suchas 1,4-dioxane or THF preferably 1,4-dioxane), alkyl halide or mesylate(1-30 equiv, preferably 8-16 equiv), and/or TBAB (0.05-2 equiv,preferably 0.08-1.5 equiv). This process is repeated until the reactionproceeds no further. After cooling to ambient temperature, the reactionis worked up using one of the following methods. Method 1: An organicsolvent such as EtOAc or DCM is added with the optional addition ofwater or brine and the layers are separated. The aqueous layer is thenoptionally extracted with additional organic solvent such as EtOAc orDCM. The combined organic layers are optionally washed with brine orwater, dried over anhydrous MgSO₄ or Na₂SO₄, filtered or decanted, andconcd under reduced pressure. Method 2: A reaction mixture containing aprecipitate may be filtered. To the filtrate is added an organic solventsuch as EtOAc or DCM with the optional addition of water or brine andthe layers are separated. The aqueous layer is then optionally extractedwith additional organic solvent such as EtOAc or DCM. The combinedorganic layers are optionally washed with brine or water, dried overanhydrous MgSO₄ or Na₂SO₄, filtered or decanted, and concd under reducedpressure.

Illustration of General Procedure HHHH Preparation #HHHH.13-(((1R,3R,4S)-3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyloxy)methyl)-5-methylisoxazole

A mixture of3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanol(0.072 g, 0.179 mmol, Example #35, Step H), KOH aqueous (50% w/v 0.118g, 2.10 mmol) and 1,4-dioxane (0.1 mL) was heated to about 70° C. To thereaction mixture was added 3-(bromomethyl)-5-methylisoxazole (0.063 g,0.359 mmol, Maybridge) and TBAB (0.004 g, 0.01 mmol) and the reactionmixture was stirred for about 24 h. To the reaction mixture was added3-(bromomethyl)-5-methylisoxazole (0.063 g, 0.36 mmol, Maybridge) andaqueous KOH (50% w/v 0.118 g, 2.10 mmol) and stirring was continued forabout 24 h. The reaction was cooled to ambient temperature and EtOAc (10mL) and water (5 mL) were added. The layers were separated and theaqueous layer was extracted with EtOAc (10 mL). The combined organiclayers were dried over anhydrous MgSO₄, filtered, and concd underreduced pressure. The crude material was purified by silica gelchromatography eluting with a gradient of 0-5% MeOH in DCM to give3-(((1R,3R,4S)-3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyloxy)methyl)-5-methylisoxazole(0.064 g, 72%): LC/MS (Table 1, Method b) R_(t)=2.58 min; MS m/z: 497(M+H)⁺.

General Procedure IIII: Formation of a Mesylate

To a solution of an alcohol (preferably 1 equiv) in an organic solventsuch as DCM an organic base such as TEA or Hunig's base (1-4 equiv,preferably 2 equiv) is added at about 0-40° C. (preferably roomtemperature) followed by a dropwise addition at this temperature ofmesyl chloride (1-2 equiv preferably 1.1 equiv). In cases where thereaction mixture is cooled to below rt, it is stirred at thistemperature for about 1-3 h (preferably about 2 h) and then optionallywarmed up to ambient temperature while stirring overnight. The productcould be worked up by one of the following methods. 1). The reactionmixture is concentrated. 2). The reaction mixture is washed withsaturated aqueous NaHCO₃ and brine, dried over anhydrous MgSO₄,filtered, and concentrated.

Illustration of General Procedure IIII Preparation #IIII.13-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylmethanesulfonate

Mesyl chloride (0.067 mL, 0.866 mmol) was added dropwise to a solutionof3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanone(0.316 g, 0.787 mmol, Example #35 Step H) and TEA (0.219 mL, 1.57 mmol)in DCM (8 mL), and the reaction mixture was stirred at rt overnight. Thesolvent was removed under reduced pressure and the residue purified bysilica gel column chromatography (0 to 60% EtOAc in DCM) to yield3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylmethanesulfonate (0.29 g, 77%) as a white amorphous solid: LC/MS (Table1, Method a) R_(t)=2.53 min; MS m/z 480 (M+H)⁺.

General Procedure JJJJ: Displacement of an Alkyl Mesylate, Tosylate, orHalide with a Nucleophile

A round bottom flask is charged with an alkyl mesylate, tosylate, orhalide (preferably 1 equiv) and an organic solvent such as DMF, DMA, NMPor DMSO (preferably DMF). To the reaction flask is added the sodium orpotassium salt (preferably the sodium salt) of the nucleophile such as,but not limited to, an azide, cyanide, thioacetate, pyrazole andtriazole (1-10 equiv, preferably 5.0 equiv) in portions. When thenucleophile is not already the sodium or potassium salt, a base such as60% NaH in mineral oil (1-10 equiv, preferably an equimolar amount tothe nucleophile used) is added. The mixture is stirred at about 10-100°C. (preferably ambient temperature) for about 1-24 h (preferably about20 h). If the reaction does not go to completion as monitored by HPLC,LC/MS, or TLC, additional nucleophile and/or base is used (5-300% of theoriginal amount used, preferably 10%) may be added and the reaction iscontinued for about 0.5-24 h (preferably about 2 h). The reaction ispartitioned between an organic solvent such as EtOAc or DCM (preferablyEtOAc) and water. The layers are separated and the organic solution isdried over anhydrous MgSO₄ or Na₂SO₄, filtered, and concentrated underreduced pressure to provide the target compound.

Illustration of General Procedure JJJJ Preparation #JJJJ.11-((1S,2R,4R)-4-azido-2-ethylcyclopentyl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine

A round bottom flask was charged with3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylmethanesulfonate (0.83 g, 1.7 mmol, Preparation #IIII.1) and DMF (7.0mL). To the reaction flask was added sodium azide (0.56 g, 8.6 mmol).The mixture was stirred at ambient temperature for about 20 h. Anotherportion of sodium azide (0.056 g, 0.86 mmol) was added and the reactionwas stirred for about 2 h. The reaction was partitioned between EtOAc(20 mL) and water (20 mL). The layers were separated and the organicsolution was dried over anhydrous MgSO4, filtered, and concentratedunder reduced pressure to give1-(−4-azido-2-ethylcyclopentyl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine(0.65 g, 88%) as a brown oil: LC/MS (Table 1, Method b) R_(t)=2.85 min;MS m/z: 427 (M+H)⁺.

General Procedure KKKK: Cyclization of a Ketone Using TFAA or PFPAA

To a ketone (preferably 1 equiv) optionally dissolved in an organicsolvent such as acetonitrile or DCM (preferably acetonitrile) is addedTFA/TFAA (2-100 equiv/10-60 equiv, preferably 2 equiv/10 equiv) or PFPAA(2-30 equiv, preferably 10 equiv) or 2,2,3,3,3-pentafluoropropanoicacid/PFPAA (1-10 equiv/5-50 equiv, preferably 2 equiv/10 equiv) at about0° C. to 50° C. (preferably ambient temperature). The reaction is warmedand stirred at about 0° C. to about 80° C. (preferably about 60° C.) forabout 0.5-48 h (preferably about 2-4 h). Additional TFAA or PFPAA (2-10equiv) can be added to complete the reaction. MeOH is optionally addedto quench the reaction. The reaction mixture is concentrated underreduced pressure. Alternatively, the crude mixture may be optionallyconcentrated before partitioning between an aqueous solution of aninorganic base (for example aqueous NaHCO₃ or K₂CO₃) and an organicsolvent (for example EtOAc or DCM). The layers are separated and theaqueous layer is extracted further with organic solvent (such as EtOAcand/or DCM). The combined organic layers are optionally washed withbrine, dried over anhydrous MgSO₄ or Na₂SO₄, filtered, and concentratedto dryness under reduced pressure.

Illustration of General Procedure KKKK Preparation #KKKK.13-Tosyl-8-(2-tosyl-2-azaspiro[3.3]heptan-6-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine

To a solution of2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)-1-(2-tosyl-2-azaspiro[3.3]heptan-6-yl)ethanone(0.631 g, 1.089 mmol, prepared using R with2-tosyl-2-azaspiro[3.3]heptane-6-carboxylic acid [prepared as describedin J. Org. Chem, 2010, 75, 5941] and trimethylsilyl diazomethane, S withExample #3 Step E, E with TFA) in MeCN (5 mL) was added PFPAA (2.15 mL,10.9 mmol). The mixture was heated at about 60° C. for about 2 h. Thereaction mixture was partitioned between DCM (30 mL) and saturatedaqueous NaHCO₃ (50 mL). The layers were separated and the aqueous layerwas extracted further with DCM (2×30 mL). The combined organic layerswere dried over anhydrous MgSO₄, filtered, and concentrated to drynessunder reduced pressure. The crude material was purified using silica gelflash chromatography eluting with a gradient of 50-100% EtOAc in heptaneto give3-tosyl-8-(2-tosyl-2-azaspiro[3.3]heptan-6-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine(0.467 g, 76%) as a white solid: LC/MS (Table 1, Method b) R_(t)=2.53min; MS m/z 562 (M+H)⁺.

General Procedure LLLL: Formation of a Bromoketone from a Ketone or anAldehyde

To a ketone or an aldehyde (preferably 1 equiv) in an organic solvent(DCM or DCE, preferably DCM) at about −20 to 20° C. (preferably about 0°C.), an organic base such as TEA or DIEA (preferably DIEA, 1-20 equiv,preferably 5-10 equiv) is added, followed by addition of trimethylsilyltrifluoromethanesulfonate (1-8 equiv, preferably 4.5 equiv). Thereaction is stirred at the same temperature for about 0.5 to 6 h(preferably about 1 h). A suitable organic solvent (such as EtOAc orDCM) is optionally added. An aqueous solution (such as saturated aqueousNaHCO₃ or water) is added. The layers are separated, the aqueous layeris optionally extracted with additional organic solvent (such as EtOAcor DCM) and the organic layer or combined organic layers are dried overanhydrous Na₂SO₄ or MgSO₄, filtered, and concd under reduced pressure togive a TMS-protected enol intermediate. The intermediate is dissolved inan organic solvent (DCM or DCE, preferably DCM) at about −20 to 60° C.(preferably rt) and an inorganic base such as NaHCO₃ or Na₂CO₃(preferably NaHCO₃, 1-20 equiv, preferably 4 equiv) and NBS (1-3 equiv,preferably 1 equiv) are added. The reaction is stirred at the sametemperature for about 1-48 h (preferably about 18 h). A suitable organicsolvent (such as EtOAc or DCM) and an aqueous solution (such assaturated aqueous NaHCO₃ or water) are added, the layers are separated,and the organic solution is dried over anhydrous Na₂SO₄ or MgSO₄,filtered, and concd under reduced pressure.

Illustration of General Procedure LLLL Preparation #LLLL.1t-butyl-(cis-5-(2-bromoacetyl)-4-methyltetrahydrofuran-2-yl)methyl(3,3,3-trifluoropropylsulfonyl)carbamate

To a solution of t-butyl(cis-5-acetyl-4-methyltetrahydrofuran-2-yl)methyl(3,3,3-trifluoropropylsulfonyl)carbamate(0.54 g, 1.3 mmol, prepared using M.1 from Preparation #MMMM.1) in DCM(5 mL) at about 0° C. was added DIEA (2.03 mL, 11.6 mmol) andtrimethylsilyl trifluoromethanesulfonate (1.06 mL, 5.82 mmol). Thereaction was stirred at about 0° C. for about 1 h. Saturated aqueousNaHCO₃ (10 mL) was added and the layers were separated. The aqueouslayer was extracted with DCM (2×10 mL). The combined organic extractswere dried over anhydrous MgSO₄, filtered, and concd under reducedpressure. The residue was dissolved in DCM (5 mL) and NaHCO₃ (0.435 g,5.17 mmol) and NBS (0.230 g, 1.294 mmol) were added. The reaction wasstirred at ambient temperature for about 18 h. The reaction mixture waspartitioned between water (30 mL) and DCM (30 mL). The aqueous layer wasextracted with DCM (2×30 mL). The combined organic extracts were driedover anhydrous MgSO₄, filtered, and concd under reduced pressure. Theproduct was purified by silica gel chromatography eluting with agradient of 0-30% EtOAc in heptane to givet-butyl-(cis-5-(2-bromoacetyl)-4-methyltetrahydrofuran-2-yl)methyl(3,3,3-trifluoropropylsulfonyl)carbamate(0.472 g, 73%) as a yellow solid: LC/MS (Table 1, Method b) R_(t)=2.76min; MS m/z: 494, 496 (M−H)⁻.

General Procedure MMMM: Formation of a Ketone from a Weinreb Amide

To a Weinreb amide (preferably 1 equiv) in an organic solvent (forexample DCM, MeCN, 1,4-dioxane or THF, preferably THF) is added aGrignard or an alkyl lithium reagent (1-10.0 equiv, preferably 6 equiv)at about −30 to 40° C. (preferably about −10° C.). The reaction mixtureis stirred at about −30 to 40° C. (preferably about −10° C.) for about1-24 h (preferably about 5 h). The reaction mixture is quenched with anaqueous acid (such as aqueous HCl) and then water, partitioned betweenan organic solvent (such as Et₂O, EtOAc or DCM) and water. The layersare separated and the aqueous layer is extracted with additional organicsolvent and the combined organic layers may be optionally washed withbrine. The organic layer is optionally dried over anhydrous Na₂SO₄ orMgSO₄, and then decanted or filtered prior to concentrating underreduced pressure.

Illustration of General Procedure MMMM Preparation #MMMM.1N-((cis-5-acetyl-4-methyltetrahydrofuran-2-yl)methyl)-3,3,3-trifluoropropane-1-sulfonamide

To a solution ofcis-N-methoxy-N,3-dimethyl-5-((3,3,3-trifluoropropylsulfonamido)methyl)tetrahydrofuran-2-carboxamide(0.70 g, 1.9 mmol, prepared using E from Preparation #43 with HCl, Kwith 3,3,3-trifluoropropane-1-sulfonyl chloride (Matrix), Z with NaOH, Hwith N,O-dimethylhydroxylamine hydrochloric acid) in THF (5 mL) wasadded methylmagnesium bromide (3 N in Et₂O, 3.86 mL, 11.6 mmol) dropwiseat about −10° C. The reaction mixture was stirred at about −10° C. forabout 5 h. Aqueous HCl (1 N, 9.66 mL, 9.66 mmol) was added to quench thereaction. The reaction mixture was partitioned between water (10 mL) andDCM (20 mL). The layers were separated and the aqueous layer wasextracted with DCM (2×20 mL). The combined organic extracts were concdunder reduced pressure. The product was purified by silica gelchromatography eluting with a gradient of 0-100% EtOAc in heptane togiveN-((cis-5-acetyl-4-methyltetrahydrofuran-2-yl)methyl)-3,3,3-trifluoropropane-1-sulfonamide(0.57 g, 93%) as a clear oil: LC/MS (Table 1, Method b) R_(t)=2.02 min;MS m/z: 318 (M+H)⁺.

General Procedure NNNN: Formation of β-Hydroxysulfonamide from a Ketone

To an optionally substituted methyl sulfonamide (1-8 equiv, preferably1.5 equiv) in an organic solvent (DCM or THF, preferably THF) at about−20 to 20° C. (preferably about 0° C.), an alkyl lithium reagent (forexample n-BuLi, t-BuLi or LDA (preferably n-BuLi, 1-20 equiv, preferably1-2 equiv) is added. The reaction is stirred at about −20 to 20° C.(preferably about 0° C.) for about 0.5-72 h (preferably about 1 h). Theresulting solution is added dropwise to a solution of ketone (preferably1.0 equiv) in an organic solvent (DCM or THF, preferably THF) at about−20 to 20° C. (preferably about 0-5° C.). The reaction is stirred atabout −20 to 20° C. (preferably about 0-5° C.) for about 1-72 h(preferably about 48 h). A suitable organic solvent (such as EtOAc orDCM) and an aqueous solution (such as saturated aqueous NaHCO₃ or water)are added, the layers are separated, and the organic solution is driedover anhydrous Na₂SO₄ or MgSO₄, filtered, and concd under reducedpressure.

Illustration of General Procedure NNNN Preparation #NNNN.13-Ethyl-1-(morpholinosulfonylmethyl)-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanol

To a solution of 4-(methylsulfonyl)morpholine (0.217 g, 1.314 mmol,Preparation #41) in THF (4 mL) at about 0° C. was added n-BuLi (2.5 M inhexanes, 0.53 mL, 1.3 mmol). The reaction mixture was stirred at about0° C. for about 1 h. The resulting solution was added dropwise to asolution of3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanone(0.350 g, 0.876 mmol, Example #35 Step G) in THF (4 mL) at about 0° C.The reaction mixture was maintained at about 4° C. in a refrigerator forabout 48 h. The reaction mixture was partitioned between water (5 mL)and DCM (5 mL). The layers were separated and the aqueous solution wasextracted with DCM (2×5 mL). The combined organic extracts were concdunder reduced pressure. The product was purified by silica gelchromatography eluting with a gradient of 0-2% MeOH/DCM, then by RP-HPLC(Table 1, Method 1) to give3-ethyl-1-(morpholinosulfonylmethyl)-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanol(0.17 g, 34%) as a yellow oil: LC/MS (Table 1, Method b) R_(t)=2.32 &2.42 min; MS m/z: 565 (M+H)⁺.

General Procedure OOOO: Formation of a Carbonate

To an alcohol (preferably 1 equiv) in an organic solvent (preferablypyridine) at about −20° C. to 80° C. (preferably ambient temperature) isadded DMAP (0.1-5 equiv, preferably 0.3 equiv) and a chloroformate (1-10equiv, preferably 2 equiv). The reaction mixture is stirred at about−20° C. to 80° C. (preferably ambient temperature) for about 1-16 h(preferably about 1 h). The reaction mixture is either concd underreduced pressure or optionally filtered, diluted with an organic solvent(preferably EtOAc), washed with water and an aqueous base (such assaturated aqueous Na₂CO₃ or NaHCO₃) or saturated brine, dried overanhydrous Na₂SO₄ or MgSO₄, filtered, and concd under reduced pressure.

Illustration of General Procedure OOOO Preparation #OOOO.1(1R,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl-4-nitrophenylcarbonate

To a scalemic mixture enriched in(1R,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanol(1.20 g, 2.82 mmol, Example #41, Step N) in pyridine (10 mL) was addedDMAP (0.103 g, 0.846 mmol) and 4-nitrophenyl chloroformate (0.853 g,4.23 mmol). The resulting mixture was stirred at ambient temperature forabout 1 h. The reaction mixture was concentrated and purified usingsilica gel chromatography eluting with 0-30% EtOAc in DCM to give ascalemic mixture enriched in(1R,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl4-nitrophenyl carbonate (0.72 g. 43%): LC/MS (Table 1, Method b)R_(t)=2.64 min; MS m/z: 591 (M+H)⁺.

General Procedure PPPP: Formation of a Carbamate Followed by SulfonamideHydrolysis

To a carbonate (preferably 1 equiv) in an organic solvent (preferably1,4-dioxane) at about −20 to 60° C. (preferably at ambient temperature)is added an amine (2-10 equiv, preferably 5 equiv) and optionally DMAP(0-5 equiv, preferably 0 equiv). After about 1-16 h (preferably about 1h), aqueous sodium hydroxide (1-2 N, preferably 1 N; 1-10 eq, preferably4 equiv) is added. The reaction mixture is stirred at about 25-100° C.(preferably about 60° C.) for about 10 min-5 h (preferably about 30 min)and, if the reaction was heated, cooled to ambient temperature. Thereaction mixture is either concd under reduced pressure or the layersare separated and the aqueous layer is extracted with an organic solvent(preferably DCM). The combined organic extracts are washed with water,an aqueous base (such as saturated aqueous Na₂CO₃ or NaHCO₃), orsaturated brine, dried over anhydrous Na₂SO₄ or MgSO₄, filtered, andthen concd under reduced pressure.

Preparation #PPPP.1(1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylcyclopropylcarbamate

To a scalemic mixture enriched in(1R,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl4-nitrophenyl carbonate (Example #41 Step O, 0.211 g, 0.357 mmol) in1,4-dioxane (1.5 mL) was added cyclopropylamine (0.102 g, 1.79 mmol).After about 1 h, 1N aqueous sodium hydroxide (1.5 mL, 1.5 mmol) wasadded and the reaction mixture was heated at about 60° C. for about 30min then cooled to ambient temperature. The layers were separated andthe aqueous layer was extracted with DCM (3×5 mL). The combined organiclayers were concd under reduced pressure. The residue was purified bysilica gel chromatography eluting with 0-10% MeOH in EtOAc to give(1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylcyclopropylcarbamate (0.085 g, 67%): LC/MS (Table 1, Method b)R_(t)=1.73 min; MS m/z: 355 (M+H)⁺.

TABLE PPPP.1 Examples prepared from a scalemic mixture enriched in(1R,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl4-nitrophenyl carbonate (Example #41 Step O) R_(t) min (Table 2, m/zESI+ Amine Product Example # Method) (M + H)⁺ 3,3-difluoroazetidinehydrochloride [Matrix]

PPPP.1.1 1.94 (b) 391 2-aminoacetonitrile

PPPP.1.2 1.64 (b) 354 dimethylamine

PPPP.1.3 1.75 (b) 343 oxetan-3-amine

PPPP.1.4 1.54 (b) 371 cyclobutanamine

PPPP.1.5 1.89 (b) 369 2-aminoacetonitrile

PPPP.1.6 1.42 (b) 372 piperidin-4-ol

PPPP.1.7 1.39 (b) 399 2,2,2- trifluoroethanamine

PPPP.1.8 1.80 (b) 397

TABLE PPPP.2 Examples prepared from a scalemic mixture enriched in(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylcyclobutylcarbamate (Example #42 Step N) R_(t) min m/z Exam- (Table 2,ESI+ Amines Product ple # Method) (M + H)⁺ dimethylamine

PPPP.2.1 1.66 (b) 343 cyclobutanamine

PPPP.2.2 1.17 (c) 369 piperidin-4-ol

PPPP.2.3 1.63 (b) 399 2-aminoacetonitrile

PPPP.2.4 1.67 (b) 354 cyclopropanamine

PPPP.2.5 1.75 (b) 355 2,2,2- trifluoroethanamine

PPPP.2.6 1.90 (b) 397 3,3-difluoroazetidine hydrochloride [Matrix]

PPPP.2.7 1.91 (b) 391 piperidine-4- carbonitrile

PPPP.2.8 1.81 (b) 408 azetidine-3- carbonitrile hydrochloride [Astatech]

PPPP.2.9 1.76 (b) 380 phenylmethanamine

PPPP.2.10 2.01 (b) 405 oxetan-3-amine

PPPP.2.11 1.62 (b) 371 1- aminocyclopropane- carbonitrile hydrochloride[Astatech]

PPPP.2.12 1.77 (b) 380 3-methyloxetan-3- amine [Synthonix]

PPPP.2.13 1.69 (b) 385 (R)-pyrrolidin-3-ol

PPPP.2.14 1.62 (b) 385 (S)-pyrrolidin-3-ol

PPPP.2.15 1.61 (b) 385 4-fluoropiperidine hydrochloride

PPPP.2.16 1.92 (b) 401 2,2- difluoroethanamine [Matrix]

PPPP.2.17 1.82 (b) 379 piperidine

PPPP.2.18 1.41 (v) 383 3-fluoroazetidine hydrochloride [Acesys]

PPPP.2.19 1.81 (b) 373 1- methylcyclobutanamine [Matrix]

PPPP.2.20 1.98 (b) 383 1- (aminomethyl) cyclopropanol [ChemPacific]

PPPP.2.21 1.72 (b) 385 N-methyloxetan-3- amine [Synthonix]

PPPP.2.22 1.68 (b) 385 (3-methyloxetan-3- yl)methanamine [Synthonix]

PPPP.2.23 1.68 (b) 399 2-methylpropan-2- amine

PPPP.2.24 0.81 (u) 371 2,2-dimethylpropan- 1-amine

PPPP.2.25 0.84 (u) 385 2- methoxyethanamine

PPPP.2.26 0.66 (u) 373 (3,5- bis(trifluoromethyl) phenyl)methanamine

PPPP.2.27 0.96 (u) 541 N1,N1,N2- trimethylethane-1,2- diamine

PPPP.2.28 0.56 (u) 400 N1,N1,N3- trimethylpropane-1,3- diamine

PPPP.2.29 0.59 (u) 414 N-benzylpropan-2- amine

PPPP.2.30 0.92 (u) 447 (R)-piperidin-3-ol

PPPP.2.31 0.70 (u) 399 1-methylpiperazine

PPPP.2.32 0.53 (u) 398 1-(piperazin-1- yl)ethanone

PPPP.2.33 0.66 (u) 426 1-(2- fluorophenyl) piperazine

PPPP.2.34 0.89 (u) 478 pyridin-2- ylmethanamine

PPPP.2.35 0.54 (u) 406 pyridin-3- ylmethanamine

PPPP.2.36 0.54 (u) 406 pyridin-4- ylmethanamine

PPPP.2.37 0.54 (u) 406 2-methylpropan-1- amine

PPPP.2.38 0.80 (u) 371 (S)-(tetrahydrofuran- 2-yl)methanamine

PPPP.2.39 0.71 (u) 399 (R)-(tetrahydrofuran- 2-yl)methanamine

PPPP.2.40 0.71 (u) 399 3- (cyclopropylamino) propanenitrile

PPPP.2.41 0.72 (u) 408 diisobutylamine

PPPP.2.42 0.97 (u) 427 azetidine

PPPP.2.43 0.72 (u) 355 2-methoxy-N- methylethanamine

PPPP.2.44 0.72 (u) 387 morpholine

PPPP.2.45 0.70 (u) 385 thiomorpholine

PPPP.2.46 0.78 (u) 401 N1,N1 dimethylethane-1,2- diamine

PPPP.2.47 0.53 (u) 386 N1,N1- methylpropane-1,3- diamine

PPPP.2.48 0.54 (u) 400 2-(pyrrolidin-1- yl)ethanamine

PPPP.2.49 0.55 (u) 412 3-(pyrrolidin-1- yl)propan-1-amine

PPPP.2.50 0.56 (u) 426 2-(piperidin-1- yl)ethanamine

PPPP.2.51 0.57 (u) 426 3-(piperidin-1- yl)propan-1-amine

PPPP.2.52 0.58 (u) 440 2- morpholino- ethanamine

PPPP.2.53 0.54 (u) 428 3- morpholinopropan- 1-amine

PPPP.2.54 0.55 (u) 442

General Procedure QQQQ: Oxidation of an Alkyl Thioacetate to an AlkylSulfonic Acid

To a mixture of the alkyl thioacetate (preferably 1 equiv) and formicacid (30-100 equiv, preferably 36 equiv) and aqueous H₂O₂ (˜30%, 3-10equiv, preferably 5 equiv) are added dropwise. The reaction is stirredat ambient temperature for about 1-8 h (preferably about 2 h). Thereaction is quenched with saturated aqueous Na₂S₂O₃ and is extractedwith an organic solvent such as DCM. The organic extract is concd underreduced pressure. The resulting residue is optionally partitionedbetween an organic solvent such as EtOAc and brine. The aqueous extractis concd under reduced pressure and the resulting residue is optionallytriturated in an organic solvent or mixture of organic solvents such asMeOH, DCM or MeOH/DCM (preferably MeOH/DCM) and filtered. The filtrateis concd under reduced pressure and optionally purified.

Illustration of General Procedure QQQQ Preparation #QQQQ.1(1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentane-1-sulfonicacid

To a mixture ofS-(1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylethanethioate (0.28 g, 0.58 mmol, prepared using P from Preparation #25,Step E and DIBAL-H; IIII, and JJJJ with potassium thioacetate) andformic acid (0.80 mL, 20.8 mmol) was added aqueous H₂O₂ (−30%, 0.30 mL,2.9 mmol) dropwise. The reaction was stirred at ambient temperature forabout 2 h. The reaction was quenched with saturated aqueous Na₂S₂O₃ (25mL) and extracted with DCM (2×25 mL). The combined extracts were concdunder reduced pressure. The resulting residue was partitioned betweenEtOAc and brine (25 mL each). The aqueous extract was concd underreduced pressure. The resulting residue was partially dissolved inMeOH/DCM (1:1, 50 mL), filtered and concd under reduced pressure. Theresulting residue was purified by RP-HPLC (Table 1, Method y) to give(1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentane-1-sulfonicacid (0.058 g, 20%) as an off-white solid: LC/MS (Table 1, Method b)R_(t)=1.60 min; MS m/z: 490 (M+H)⁺.

General Procedure RRRR: Cyclization of a Diamine with Cyanogen Bromide

To a mixture of a substituted diamine (1 equiv) in an organic solvent(for example, MeOH or EtOH, preferably MeOH) is added cyanogen bromideor cyanogen bromide in MeCN (1-10 equiv, preferably 8.0 equiv). Themixture is stirred at ambient temperature for about 1-24 h (preferablyabout 16 h) and the solvent is removed under reduced pressure.

Illustration of General Procedure RRRR Preparation #RRRR.1*N-((1S,3S,4R)-3-(2-amino-6-tosylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-4-ethylcyclopentyl)cyclopropanesulfonamide

To a solution ofN-((1S,3S,4R)-3-(5-amino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-4-ethylcyclopentyl)cyclopropanesulfonamide(0.200 g, 0.301 mmol, Example #23 Step I) in MeOH (3.0 mL) was addedcyanogen bromide (5 M in MeCN, 0.482 mL, 2.41 mmol) dropwise. Thereaction was stirred at ambient temperature for about 16 h. The solventwas removed under reduced pressure and the residue was purified bysilica gel chromatography eluting with a gradient of 0-10% MeOH in DCMto giveN-((1S,3S,4R)-3-(2-amino-6-tosylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-4-ethylcyclopentyl)cyclopropane-sulfonamide(0.11 g, 67%) as a brown solid: LC/MS (Table 1, Method a) R_(t)=2.00min; MS m/z: 543 (M+H)⁺.

General Procedure SSSS: Cyclization of a Diamine with NaNO₂

A mixture of a diamine (preferably 1 equiv) and an acidic aqueoussolution (such as 6 M HCl in water) is cooled to about 0° C. Then anaqueous solution of NaNO₂ (1-5 equiv, preferably 1-2 equiv) is added andthe reaction is maintained at about 0° C. for about 1-6 h (preferablyabout 2-3 h) and then warmed slowly to rt or is allowed to warm slowlyto rt immediately following the addition. After about 1-18 h (preferablyabout 12-16 h), the reaction is filtered, while washing with water, tocollect the solid.

Illustration of General Procedure SSSS Preparation #SSSS.1*N-((1S,3R,4S)-3-ethyl-4-(6-tosylpyrrolo[2,3-b][1,2,3]triazolo[4,5-d]pyridin-1(6H)-yl)cyclopentyl)cyclopropanesulfonamide

A mixture ofN-((1S,3S,4R)-3-(5-amino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-4-ethylcyclopentyl)cyclopropanesulfonamide(0.15 g, 0.23 mmol, Example #23 Step I) and aqueous HCl (6 N, 1.0 mL,6.00 mmol) was cooled to about 0° C. A solution of NaNO₂ (0.022 g, 0.32mmol) in water (0.2 mL) was added and the reaction was stirred at about0° C. After about 3 h, the reaction was warmed to rt. After about 15.5h, the reaction was filtered to collect the yellow solid by vacuumfiltration, while washing with water (10 mL). The crude solid waspurified by silica gel chromatography eluting with 0-20% EtOAc in DCM togiveN-((1S,3R,4S)-3-ethyl-4-(6-tosylpyrrolo[2,3-b][1,2,3]triazolo[4,5-d]pyridin-1(6H)-yl)cyclopentyl)cyclopropanesulfonamide(0.088 g, 74%): LC/MS (Table 1, Method a) R_(t)=2.44 min; MS m/z: 529(M+H)⁺.

General Procedure TTTT: Formation of a Squaramide

A mixture of a 3-amino-4-methoxycyclobut-3-ene-1,2-dione (preferably 1equiv), an amine (1-5 equiv, preferably 2 equiv), an organic base suchas DIEA or TEA (1-10 equiv, preferably 5-6 equiv of DIEA), and asuitable organic solvent such as MeOH or DCE (preferably MeOH) washeated at about 40 to 65° C. (preferably about 50° C.). After about 1-24h (preferably about 12-18 h), the reaction is filtered, while washingwith water, to collect the solid.

Illustration of General Procedure TTTT Preparation #TTTT.1*3-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)-4-(3,3,3-trifluoropropylamino)cyclobut-3-ene-1,2-dione

A mixture of3-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)-4-methoxycyclobut-3-ene-1,2-dione(0.090 g, 0.17 mmol, Preparation #29), 3,3,3-trifluoropropan-1-aminehydrochloride (0.050 g, 0.337 mmol, Fluorochem Limited), DIEA (0.18 mL,1.0 mmol) and MeOH (1.2 mL) was heated at about 50° C. After about 18 h,the reaction was cooled to rt. The solid was collected via vacuumfiltration, while washing with MeOH (about 3-5 mL), and then dried in avacuum oven at about 60° C. to give3-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)-4-(3,3,3-trifluoropropylamino)cyclobut-3-ene-1,2-dione(0.083 g, 79%) as an off-white solid: LC/MS (Table 1, Method a)R_(t)=2.27 min; MS m/z: 616 (M+H)⁺.

General Procedure UUUU: Reduction of an Azide to an Amine

To a solution of an azide (preferably 1 equiv) in a suitable organicsolvent (such as THF or 1,4-dioxane, preferably THF) and water is addedtriphenylphosphine (1-2 equiv, preferably 1.2 equiv). The reactionmixture is stirred at about room temperature −80° C. (preferably about45° C.) for about 1-24 h (preferably about 7 h). If heated, the reactionmixture is cooled to room temperature. The reaction mixture is worked upusing one of the following methods. Method 1. The reaction mixture isdiluted in an organic solvent (such as DCM or EtOAc) and water is added.The layers are separated and the organic solution is optionally washedwith water and/or brine, dried over anhydrous MgSO₄ or Na₂SO₄, filtered,and the solvent is removed under reduced pressure. Method 2. Thereaction mixture is concentrated under reduced pressure.

Illustration of General Procedure UUUU Preparation #UUUU.13-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine

A round bottom flask was charged with1-(−4-azido-2-ethylcyclopentyl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine(0.650 g, 1.52 mmol, prepared using D from Preparation #25 with NaOH,KK, P with NaBH₄, IIII, JJJJ with NaN₃), THF (8.0 mL), and water (1.6mL). To the flask was added triphenylphosphine (0.480 g, 1.83 mmol). Thereaction mixture was heated to about 45° C. for about 7 h. The reactionmixture was cooled to room temperature and EtOAc (20 mL) and water (15mL) were added. The layers were separated and the organic solution wasdried over anhydrous MgSO₄, filtered, and concentrated under reducedpressure to give an oil that solidified upon standing. The crudematerial was purified via flash silica gel chromatography eluting with agradient of 1-10% DCM/MeOH/DEA (900:90:10) in DCM. The productcontaining fractions were combined and concentrated under reducedpressure to give an oil that was then dried on a vacuum pump overnightto give3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamineas a tacky oil (0.49 g, 80%): LC/MS (Table 1, Method b) R_(t)=1.85 min;MS m/z 401 (M+H)⁺.

General Procedure VVVV: Formation of a Ketone from a Heteroaryl Halide.

To a solution of a heteroaryl halide (preferably 1 equiv) in an organicsolvent (for example THF) at about −100° C. to 0° C. (preferably about−78° C.) is added an alkyl lithium base (1-2 equiv) (preferablysec-butyllithium, 1.3 equiv) drop-wise. The reaction mixture is stirredat about −100° C. to 0° C. (preferably about −78° C.) for about 15 minto 5 h (preferably about 1 h). A solution of an acylating agent (such asan acid chloride, Weinreb amide or acylimidazole for example, preferablyan acid chloride, 1-3 equiv, preferably 1.5 equiv). The reaction mixtureis allowed to reach ambient temperature and water is added. The layersare separated and the aqueous layer is then extracted with an organicsolvent such as DCM or EtOAc. The combined organic layers are thenwashed with water and/or brine, dried over anhydrous MgSO₄ or NaSO₄,filtered and concentrated under reduced pressure.

Illustration of General Procedure VVVV Preparation #VVVV.1 tert-butyl4-(2-(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-oxoethyl)piperidine-1-carboxylate

To a solution of5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (0.338 g, 1.09mmol, Adesis) in THF (5.5 mL) at about −78° C. was addedsec-butyllithium (1.015 mL, 1.421 mmol) drop-wise. The reaction mixturewas stirred at about −78° C. for about 1 h then a suspension oftert-butyl 4-(2-chloro-2-oxoethyl)piperidine-1-carboxylate (0.429 g,1.64 mmol, Preparation #WWWW.1) in THF (2 mL) was added. The reactionmixture was stirred at about −78° C. for about 1 h then allowed to reachambient temperature. Water (5 mL) was added and the product wasextracted into DCM (3×10 mL). The combined organic extracts were washedwith brine and dried over anhydrous MgSO₄, filtered, and concentratedunder reduced pressure. The crude material was purified by silica gelchromatography eluting with 0-30% EtOAc in heptane to afford tert-butyl4-(2-(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-oxoethyl)piperidine-1-carboxylate(0.147 g, 25%) as a colorless oil: LC/MS (Table 1, Method r) R_(t)=3.97min; MS m/z: 534/536 (M+H)⁺

General Procedure WWWW: Formation of an Acid Chloride.

To a solution of a carboxylic acid (preferably 1 equiv) in an organicsolvent (for example DCM or DCE, preferably DCM) is added oxalylchloride (1-5 equiv, preferably 1-2 equiv) and N,N-dimethylformamide(0.05-0.5 equiv, preferably 0.1 equiv). The reaction mixture is stirredat about 0 to 50° C. (preferably ambient temperature) for about 30 minto 15 h (preferably 3 h). The solvent is removed under reduced pressureand the residue is in the next step without further purification.

Illustration of General Procedure WWWW Preparation #WWWW.1 tert-butyl4-(2-chloro-2-oxoethyl)piperidine-1-carboxylate

To a solution of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid(3.84 g, 15.78 mmol) (prepared using M from ethyl2-(piperidin-4-yl)acetate (Oakwood), Z) in DCM (79 mL) at ambienttemperature were added oxalyl chloride (1.658 mL, 18.94 mmol) and DMF(0.115 g, 1.58 mmol). The reaction mixture was stirred at ambienttemperature for about 3 h. The solvent was removed under reducedpressure to afford tert-butyl4-(2-chloro-2-oxoethyl)piperidine-1-carboxylate (4.13 g, 100%) as alight yellow solid. The product was used in the next step withoutfurther purification.

General Procedure XXXX: Formation of a Hydrazone.

To a mixture of a ketone (preferably 1 equiv) in an organic solvent(preferably EtOH) are added a hydrazine (5-100 equiv, preferably 45-55equiv) and acetic acid (1-10 equiv, preferably 4-6 equiv). The reactionmixture is stirred at ambient temperature to reflux (preferably atreflux) for about 1-24 h (preferably about 16 h). The solvent is removedunder reduced pressure and the crude material is taken up in an organicsolvent (such as DCM) and dried over anhydrous MgSO₄ or NaSO₄. Thesolvent is removed under reduced pressure.

Illustration of General Procedure XXXX Preparation #XXXX.1 tert-butyl4-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-hydrazonoethyl)piperidine-1-carboxylate

To a suspension of tert-butyl4-(2-(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-oxoethyl)piperidine-1-carboxylate(1.00 g, 1.87 mmol) in EtOH (6.4 mL) were added anhydrous hydrazine(2.94 mL, 94.0 mmol) and AcOH (0.536 mL, 9.36 mmol). The reactionmixture was stirred at reflux for about 16 h. The solvent was removedunder reduced pressure and the crude material was taken up in DCM anddried over anhydrous MgSO₄. The solvent was removed and DCM (3 mL) wasadded. The solid was removed by filtration and the filtrate was purifiedby silica gel chromatography eluting with 0-10% MeOH in DCM to affordtert-butyl4-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-hydrazonoethyl)piperidine-1-carboxylate(0.324 g, 44%) as a white solid consisting of a 1/1 mixture of E/Zisomers: LC/MS (Table 1, Method r) R_(t)=1.46 and 1.53 min; MS m/z:392/394 and 392/394 (M+H)⁺.

General Procedure YYYY: Cyclization with an α-Haloaldehyde

To an α-haloaldehyde (1-20 equiv, preferably 1.5 equiv) and a protected2-amino-5H-pyrrolo[2,3-b]pyrazine (preferably 1 equiv) is optionallyadded an organic solvent such a DCE, DMF, 1,4-dioxane, EtOH, n-butanol,or toluene (preferably n-butanol or 1,4-dioxane) with or without an acidcatalyst such as TsOH or sulfuric acid (0.05-0.2 equiv). The reactionmixture is stirred at about room temperature −150° C. (preferably about90° C.) for about 30 min-72 h (preferably about 48 h). Optionally thereaction mixture can be subjected to microwave heating at about 100-150°C. (preferably about 130° C.) for about 30 min-15 h (preferably about 9h). In cases where the reaction does not proceed to completion asmonitored by TLC, LC/MS, or HPLC, the reaction may be re-subjected toheating at about 25-100° C. (preferably about 70° C.) for about 2-48 h(preferably about 8-24 h) with the optional addition of. In cases wherethe reaction does not proceed to completion as monitored by TLC, LC/MS,or HPLC, an additional portion or portions of an α-haloaldehyde (1-20equiv, preferably 2.5 equiv) in an organic solvent such as 1,4-dioxanecan be added and the reaction continued at about rt −150° C. (preferablyabout 125° C.). The volatiles are removed under reduced pressure.Optionally the crude mixture is diluted with water, aqueous NH₄Cl, oraqueous NaHCO₃. The product may be isolated by filtration or an organicsolvent (for example, EtOAc or DCM) may be added. The layers areseparated and the aqueous layer may be extracted further with an organicsolvent (such as EtOAc and/or DCM). The combined organic layers areoptionally washed with additional aqueous solutions such as aqueousNH₄Cl, aqueous NaHCO₃, water, and/or brine, dried over anhydrous Na₂SO₄or MgSO₄, filtered, and concentrated to dryness under reduced pressure.

Illustration of General Procedure YYYY Preparation #YYYY.1 ethyl3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-carboxylate

A solution of ethyl 2-chloro-3-oxopropanoate (1.60 g, 7.65 mmol,prepared as described in US2009005359A1) and 1,4-dioxane (10.0 mL) wasadded to 5-tosyl-5H-pyrrolo[3,2-b]pyrazin-2-amine (1.45 g, 5.03 mmol,Preparation #E.1.1) under nitrogen. Anhydrous butan-1-ol (30.0 mL) wasadded, a reflux condenser was attached, and the system was sealed. Afterabout 30 min, the mixture was warmed to about 80° C. The solution wasallowed to cool to ambient temperature. A solution of ethyl2-chloro-3-oxopropanoate (2.78 g, 13.3 mmol) and 1,4-dioxane (5 mL) wasadded. After about 30 min, the reaction mixture was warmed to about 80°C. After about 30 min, the mixture was warmed to about 125° C. Afterabout 48 h, the brown solution was allowed to cool to ambienttemperature. The volatiles were removed under reduced pressure. Theresidue was purified by silica gel chromatography eluting with agradient of 5-50% EtOAc in heptane to give ethyl3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-carboxylate (1.16 g,60%): LC/MS (Table 1, Method b) R_(t)=2.52 min; MS m/z 385 (M+H)⁺.

General Procedure ZZZZ: Cyclization with SOCl₂

To the amide, urea, hydrazide, or ketone (preferably 1 equiv), neat oras a solution in an organic solvent such as 1,4-dioxane, DCE, or toluene(preferably 1,4-dioxane), optionally with a buffering co-solvent such aspyridine or TEA (preferably TEA) is added dropwise SOCl₂ (1.3-200 equiv,preferably 3 equiv) either neat or as a solution in an organic solventsuch as 1,4-dioxane, DCE, or toluene. Optionally, the reaction vessel iscooled to about −10 to 25° C. (preferably about 0° C.) during theaddition. Alternatively, the order of addition may be reversed. Thereaction mixture is warmed to about 30 to 100° C. (preferably about 80°C.) for about 0.5 to 24 h (preferably about 2 h). The reaction mixtureis allowed to cool to ambient temperature. The volatiles are optionallyremoved under reduced pressure and an organic solvent such as DCM,1,4-dioxane, or EtOAc (preferably EtOAc) is added. The organic layer iswashed with an aqueous solution such as aqueous HCl, aqueous NaOH,aqueous NaHCO₃, aqueous NH₄Cl, aqueous Na₂CO₃, or water (preferablyaqueous Na₂CO₃), with optional cooling, and the product is isolatedusing one or more of the Purification Methods described above.Optionally, subsequent removal of protecting groups can be performedusing General Procedures listed above.

Preparation #ZZZZ.1 tert-butyl(trans-4-46H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)methyl)cyclohexyl)methylcarbamate

Thionyl chloride (0.030 mL, 0.41 mmol) was added dropwise to a solutionof tert-butyl(trans-4-(2-oxo-2-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinyl)ethyl)cyclohexyl)methyl-carbamate(0.127 g, 0.228 mmol, prepared using M fromtrans-(4-aminomethylcyclohexyl)acetic acid hydrochloride [AstaTech], Hfrom Example #1, Step D, HATU, TEA), TEA (0.160 mL, 1.15 mmol), and1,4-dioxane (2.3 mL) under nitrogen. A reflux condenser was attached andthe reaction mixture was warmed to about 80° C. After about 2 h, thesolution was cooled to ambient temperature and aqueous Na₂CO₃ (2 M, 3.4mL, 6.8 mmol) was added and the biphasic mixture was warmed to about 80°C. After about 2 h, aqueous NaOH (2 M, 0.570 mL, 1.14 mmol) was addeddue to slow rate of deprotection. After about 17 h, the mixture wasallowed to cool to ambient temperature. The reaction solution wasdiluted with water (5 mL) and then extracted with EtOAc (2×10 mL). Thecombined organics were dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by silicagel chromatography eluting with a gradient of 2-8% MeOH in DCM to givetert-butyl(trans-4-((6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)methyl)cyclohexyl)methylcarbamate(0.0565 g, 63%): LC/MS (Table 1, Method a) R_(t)=1.85 min; MS m/z: 385(M+H)⁺.

General Procedure AAAAA: Formation of a Carboxylic Acid or Ester from anAryl Halide

An aryl or heteroaryl halide (preferably 1 equiv) is dissolved orsuspended in an organic solvent such as DMF, 1,4-dioxane, THF, Et₂O, ortoluene (preferably DMF or THF). The halide may be transmetallated usinga base such a n-, t-, or sec-butyllithium (1-3 equiv) or a Grignardreagent such as isopropyl magnesium bromide (1-3 equiv) and then trappedwith CO₂ to afford the carboxylic acid following an acidic workup.Alternatively, the solution of the aryl or heteroaryl halide may betreated with a base such as Cs₂CO₃, K₂CO₃, or TEA (1-10 equiv,preferably TEA, 2 equiv). Optionally, MeOH, (1-200 equiv, preferably 50equiv) is added. A palladium source such a[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II)-CH₂Cl₂adduct, [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II),bis(triphenylphosphine)dichloropalladium, ortetrakis(triphenylphosphinepalladium(0) (0.02-1 equiv, preferably[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II)-CH₂Cl₂adduct, 0.1 equiv) is added. The mixture is placed under a CO atmosphereand then warmed to about 40-120° C. (preferably about 100° C.) for about0.5-24 h (preferably about 4.5 h). The reaction is optionally quenchedusing sodium methoxide or aqueous NaOH (1-100 equiv) and an organicsolvent (for example, EtOAc or DCM) is added. The layers are separatedand the aqueous layer may be extracted further with an organic solvent(such as EtOAc and/or DCM). The combined organic layers are optionallywashed with additional aqueous solutions such as brine, dried overanhydrous Na₂SO₄ or MgSO₄, filtered, and concentrated to dryness underreduced pressure.

Illustration of General Procedure AAAAA Preparation #AAAAA.1 methyl6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-8-carboxylate

To a solution of8-iodo-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine(0.050 g, 0.12 mmol, prepared using KK from Preparation #GGG.1.1 andNaH), TEA (0.034 mL, 0.24 mmol), MeOH (0.25 mL, 6.2 mmol), and DMF (0.6mL) purged with nitrogen was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.0098 g,0.012 mmol). The mixture was purged with CO and a balloon of CO wasattached to the reaction vessel. The mixture was warmed to about 100° C.After about 4.5 h, the solution was allowed to cool to ambienttemperature. Water (5 mL) was added and the mixture was extracted withEtOAc (2×10 mL). The combined organics were dried over anhydrous Na₂SO₄,filtered, and concentrated under reduced pressure. The crude materialwas purified by silica gel chromatography eluting with a gradient of25-75% EtOAc/heptane over 30 min to afford methyl6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-8-carboxylate(0.0311 g, 74%): LC/MS (Table 1, Method n) R_(t)=0.74 min; MS m/z: 348(M+H)⁺.

General Procedure BBBBB: Cyclization with an Orthoester

To an orthoester (1-20 equiv, preferably 10 equiv) and a protected2-hydrazinyl-5H-pyrrolo[2,3-b]pyrazine (preferably 1 equiv) isoptionally added an organic solvent such a DCE, DMF, 1,4-dioxane, ortoluene (preferably DMF) with or without an acid catalyst such as TsOHor TFA (0.05-0.2 equiv). The mixture may be left at ambient temperatureor warmed at about 30-100° C. (preferably about 100° C.) for about0.5-24 h (preferably about 17 h). The volatiles may be removed underreduced pressure. Optionally, the crude mixture may be diluted withwater, aqueous NH₄Cl, or aqueous NaHCO₃. The product may be isolated byfiltration and an organic solvent (for example, EtOAc or DCM) may beadded. Alternatively, an organic solvent may be added directly to theaqueous mixture. The layers are separated and the aqueous layer may beextracted further with an organic solvent (such as EtOAc and/or DCM).The combined organic layers are optionally washed with additionalaqueous solutions such as aqueous NH₄Cl, aqueous NaHCO₃, water, and/orbrine, dried over anhydrous Na₂SO₄ or MgSO₄, filtered, and concentratedto dryness under reduced pressure.

Illustration of General Procedure BBBBB Preparation #BBBBB.16-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine

Triethyl orthoformate (76.0 mL, 456 mmol) was added to a mixture of2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (13.8 g, 45.4 mmol,Example #1, Step D) and DMF (45 mL) under nitrogen. A reflux condenserwas attached and the mixture was warmed to about 100° C. After about 17h, the solution was allowed to cool to ambient temperature. Thevolatiles were removed under reduced pressure. The residue was slurriedin water (100 mL) and then filtered, rinsing with water. The aqueousphase was extracted with EtOAc (200 mL). The organics were dried overanhydrous Na₂SO₄, filtered, and concentrated. The material was combinedwith the precipitate and then purified by silica gel chromatographyeluting with a gradient of 0-5% MeOH in DCM to give6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (10.4 g, 73%):LC/MS (Table 1, Method n) R_(t)=0.59 min; MS m/z 314 (M+H)⁺.

General Procedure CCCCC: Stille Coupling of an Aryl or Heteroaryl Halide

To a degassed solution of a aryl, heteroaryl, or vinyl stannane(preferably 1.3 equiv) and an aryl, heteroaryl or alkeneyl halide(preferably 1 equiv) in an organic solvent such as DMF, 1,4-dioxane, ortoluene (preferably DMF) may be added a base such as Cs₂CO₃, K₂CO₃, orTEA (1-10 equiv). Optionally, additives such as LiCl (1-10 equiv,preferably 3 equiv), CsF (1-10 equiv, preferably 1.5 equiv), and/or CuI(0.05-0.5 equiv, preferably 0.2 equiv) may be added. A palladium(0)source such a tetrakis(triphenylphosphine)palladium(0),bis(dibenzylideneacetone)palladium or a palladium(II) source such asbis(triphenylphosphine)palladium(II) chloride or palladium acetate isadded (0.01-0.2 equiv, preferablytetrakis(triphenylphosphine)palladium(0), preferably 0.1 equiv). Themixture is warmed at about 40 to 150° C. (preferably about 80° C.)either thermally or using a microwave for about 0.5 to 72 h (preferablyabout 4 h). The solution is cooled to rt and volatiles may be removedunder reduced pressure and the crude mixture diluted with water, aqueousNH₄Cl, aqueous NaHCO₃ and an organic solvent such as EtOAc or DCM. If asolid was present, the resulting reaction mixture was filtered to removeit. The resulting layers of the filtrate are separated and the aqueouslayer may be extracted with additional organic solvent. The combinedorganic layers are optionally washed with additional aqueous solutionssuch as brine, then dried over anhydrous Na₂SO₄ or MgSO₄, filtered, andconcentrated to dryness under reduced pressure.

Illustration of General Procedure CCCCC Preparation #CCCCC.18-(2-(4-methylpiperazin-1-yl)pyrimidin-4-yl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine

A vial containing8-bromo-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.030g, 0.076 mmol, prepared using D from Preparation #BBBBB.1 and NaOH,GGG.1 with NBS, K.1 with TsCl and NaH),2-(4-methylpiperazin-1-yl)-4-(tributylstannyl)pyrimidine (0.054 g, 0.12mmol, Preparation #39), LiCl (0.010 g, 0.24 mmol), CuI (0.003 g, 0.02mmol), CsF (0.017 g, 0.12 mmol), andtetrakis(triphenylphosphine)palladium(0) (0.009 g, 0.008 mmol) undernitrogen was evacuated and then back-filled with nitrogen. 1,4-Dioxane(0.5 mL) was added and nitrogen was bubbled through the mixture forabout 30 min. The reaction vessel was sealed and the mixture was warmedto about 80° C. After about 4 h, the mixture was allowed to cool toambient temperature. The mixture was diluted with water (5 mL) and EtOAc(5 mL) and then filtered through a syringe filter. The layers wereseparated and the aqueous phase was extracted with EtOAc (5 mL). Thecombined organics were concentrated under reduced pressure. The residuewas purified by silica gel chromatography eluting with a gradient of0-10% MeOH in DCM over 40 min to afford8-(2-(4-methylpiperazin-1-yl)pyrimidin-4-yl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine(0.026 g, 69%): LC/MS (Table 1, Method n) R_(t)=0.56 min; MS m/z 490(M+H)⁺.

General Procedure DDDDD: Deprotection of a Cbz-Protected Amine Using aSilane

A solution of Cbz-protected amine (preferably 1 equiv) and a silane (forexample triethylsilane, t-BuMe₂SiH (preferably triethylsilane, 10-500equiv, preferably 100 equiv)) is added an organic base such as TEA orDIEA (preferably TEA, 0.1-10 equiv, preferably 0.2 equiv), and apalladium catalyst (for example palladium (II) chloride, palladium (II)acetate, tris(benzylideneacetone)dipalladium(0),bis(acetato)triphenylphosphinepalladium(II), ordichlorobis(triphenylphosphine)palladium(II); preferably palladium (II)chloride, 0.01-0.20 equiv, preferably 0.1 equiv). The reaction is heatedat about 40 to 180° C. (preferably about 120° C.) for about 1 to 48 h(preferably about 8 h). The catalyst is removed by filtration and thefiltrate is concentrated under reduced pressure. The reaction mixture isoptionally worked up by adding a suitable organic solvent (such as EtOAcor DCM) and water. The layers are separated, and the organic solution isdried over anhydrous Na₂SO₄ or MgSO₄, filtered, and concd under reducedpressure to give the target compound.

Illustration of General Procedure DDDDD Preparation #DDDDD.18-(piperidin-4-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine

A solution of benzyl4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidine-1-carboxylate(0.580 g, 1.15 mmol, prepared using R from1-(benzyloxycarbonyl)piperidine-4-carboxylic acid (Matrix), S fromExample #3 Step E, E with TFA, KKKK with PFPAA, D with NaOH, KK), TEA(0.03 mL, 0.229 mmol), palladium (II) chloride (0.020 g, 0.115 mmol) intriethylsilane (18.3 mL, 115 mmol) was heated at about 120° C. for about8 h. The catalyst was removed by filtration and the filtrate wasconcentrated under reduced pressure. The product was purified by silicagel chromatography eluting with a gradient of 0-10% (90:9:1)(MeOH/DCM/DEA) in DCM to give8-(piperidin-4-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine(0.234 g, 55%) as a brown oil: LC/MS (Table 1, Method b) R_(t)=1.93 min;MS m/z: 372 (M+H)⁺.

General Procedure EEEEE: Formation of a Guanidine

To an amine (preferably 1 equiv) in an organic solvent (for example DMF,MeCN, 1,4-dioxane or THF, preferably DMF) is added an aqueous base (forexample aqueous Na₂CO₃, NaOH, K₂CO₃ or NaHCO₃; (preferably Na₂CO₃, 2-20equiv, preferably 2-10 equiv)) or an organic base such as TEA or DIEA(preferably DIEA, 1-5 equiv, preferably 4 equiv) and addition of1H-pyrazole-1-carboximidamide hydrochloride (1-10.0 equiv, preferably 3equiv). The reaction is stirred at about 10-40° C. (preferably rt) forabout 2-90 h (preferably about 72 h) and worked up using one of thefollowing methods. Method 1: An organic solvent (such as Et₂O, EtOAc orDCM) and water are added and the layers are separated. The aqueous layeris extracted with additional organic solvent and the combined organiclayers may be optionally washed with brine, dried over anhydrous Na₂SO₄or MgSO₄, and then decanted or filtered prior to concentrating underreduced pressure. Method 2: The reaction mixture is directly purified.

Illustration of General Procedure EEEEE Preparation #EEEEE.14-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidine-1-carboximidamide

A solution of8-(piperidin-4-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine(0.100 g, 0.269 mmol, Preparation #DDDDD.1),1H-pyrazole-1-carboximidamid, hydrochloride (0.118 g, 0.807 mmol) andDIEA (0.188 mL, 1.08 mmol) in DMF (2 mL) was stirred at rt for about 72h. The reaction mixture was purified by RP-HPLC (Table 1, Method 1) togive4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidine-1-carboximidamide(0.037 g, 33%) as a brown oil: LC/MS (Table 1, Method b) R_(t)=1.82 min;MS m/z: 414 (M+H)⁺.

General Procedure FFFFF: Formation of a Sulfoxonium Ylide

To a suspension of a carboxylic acid (preferably 1 equiv) in an organicsolvent (such as THF, 2-methyl tetrahydrofuran, or MTBE, preferably THF)is added an organic base such as Hunig's base or TEA (preferably TEA)(1.2-3.5 equiv, preferably 3.5 equiv) and activating agent such as DCCor HATU (preferably HATU) (1-1.5 equiv, preferably 1.01 equiv). Thereaction is stirred at 10 to 40° C. preferably ambient temperature forabout 1-20 h (preferably about 1-2 h). In a separate flask,trimethylsulfoxonium chloride (1.25-5 equiv, preferably 3 equiv) isadded to a suspension of a base such as sodium tert-butoxide orpotassium tert-butoxide (3-5 equiv, preferably 3.15 equiv) in an organicsolvent (such as THF, 2-methyl tetrahydrofuran, or MTBE, preferablyTHF). The reaction is stirred at about 60 to 70° C. (preferably 65° C.)for about 2-4 h (preferably about 3 h). The suspension is cooled toabout −5 to 5° C. and the above activated ester solution is addeddropwise over about 20-60 min. The reaction mixture is stirred at about−5 to 5° C. for about 1-20 h (preferably about 1-2 h). The reactionmixture is quenched with water dropwise at about 0 to 40° C. (preferablyambient temperature) over about 2-50 min and stirred for about 0.2-20 h(preferably about 18 h at ambient temperature. The reaction may beconcentrated under reduced pressure to remove volatiles and thenpartitioned between an organic solvent (such as EtOAc) and water. Theaqueous layer can be optionally extracted with additional organicsolvent such as EtOAc. The combined organic layer is washed with water,dried over anhydrous Na₂SO₄ or MgSO₄, filtered, concentrated underreduced pressure to give the target compound.

Illustration of General Procedure FFFFF Preparation #FFFFF.12-(4-(Dibenzylamino)cyclohexyl)-dimethylsulfoxonium-2-oxo-ethylide

To a 250 mL flask, 4-(dibenzylamino)cyclohexanecarboxylic acid (5.6 g,17.3 mmol), HATU (6.75 g, 17.4 mmol) and TEA (8.45 mL, 60.6 mmol) in THF(60 mL) were added to give a white suspension. The reaction mixture wasstirred at ambient temperature for about 1 h. To a 500 mL flask,trimethylsulfoxonium chloride (6.82 g, 51.9 mmol) and potassiumtert-butoxide (6.44 g, 54.5 mmol) in THF (60 mL) were added to giveanother white suspension. The reaction mixture was stirred at about 65°C. for about 3 h. The reaction mixture was cooled to about 5° C. Theabove activated ester solution was added dropwise over about 50 min. Thereaction mixture was stirred at about 0-5° C. for about 90 min. Thereaction mixture was quenched by the addition of water (120 mL) dropwiseat about 0-5° C. over about 25 min. The reaction mixture was stirred atabout 0-5° C. for about 30 min, then at ambient temperature for about 18h. The mixture was concd under reduced pressure to give a whitesuspension. The suspension was partitioned between EtOAc (300 mL) andwater (200 mL). The aqueous layer was extracted with EtOAc (2×100 mL).The combined organic layer was washed with water (50 mL) and brine (3×40mL). The organic layer was dried over anhydrous Na₂SO₄ and concd underreduced pressure. The residue was dissolved in hot MeOH (100 mL) andconcd under reduced pressure. The oil was dissolved in hot MeOH (60 mL)and concd to give a white solid. The solid was dissolved in MeOH (36 mL)and water (12 mL) at about 55° C. The solution was cooled to ambienttemperature, then to about 5° C. Additional 3:1 MeOH/water (40 mL) wasadded to the suspension. The suspension was filtered, washed with 1:1MeOH/water (20 mL) then with heptane (20 mL). The collected wet cake wasdried in a heated vacuum oven at about 60° C. for about 72 h to2-(4-(dibenzylamino)cyclohexyl)-dimethylsulfoxonium-2-oxo-ethylide (5.44g, 79%) as white solid: LC/MS (Table 1, Method a) R_(t)=1.42, 1.45 min;MS m/z 398 (M+H)⁺.

General Procedure GGGGG: Reaction of a Sulfoxonium Ylide with an Amine

To a mixture of sulfoxonium ylide (preferably 1 equiv) and an amine(0.7-2 equiv, preferably 1.2 equiv) is added a catalyst (such as[Ir(COD)Cl]₂, [(COD)Ir(OMe)]₂, (COD)Ir(acac), Ir(COD)₂BF₄, Ir(COD)₂BArF,Rh₂(OAc)₂, Rh₂(TFA)₄, [Ru(cym)Cl₂]₂, RUCl₂(PPh₃)₃, RuCl₂(DMSO)₄,preferably [Ir(COD)Cl]₂ (0.01-0.1 equiv, preferably 0.04 equiv)). Adegassed organic solvent (such as DCM, DCE, MeCN, THF, 2-methyltetrahydrofuran, CHCl₃, toluene, or DMF, preferably DCE) is added. Thereaction is purged with N₂ for about 10-20 min and stirred at about20-90° C. (preferably about 70° C.) for about 1-96 h (preferably about3-6 h). Optionally, additional catalyst (preferably [Ir(COD)Cl]₂ equiv)may be added to the reaction mixture in cases where the reaction doesnot proceed to completion as monitored by TLC, LC/MS, or HPLC. Once thereaction has proceeded to an acceptable level, the reaction mixture canbe concd in vacuo to provide the product.

Illustration of General Procedure GGGGG Preparation #GGGGG.11-(4-(dibenzylamino)cyclohexyl)-2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)ethanone

To a 100 mL 2-neck round-bottomed flask,2-(4-(dibenzylamino)cyclohexyl)-dimethylsulfoxonium-2-oxo-ethylide (5.4g, 13.6 mmol, Preparation #FFFFF.1),5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-amine (4.7 g, 16.3 mmol, Preparation#E.1.1), and [Ir(COD)Cl]₂ (0.365 g, 0.543 mmol, Alfa Aesar) were added.The reaction vessel was purged with N₂ for about 10 min. To the reactionvessel, degassed DCE (25 mL) was added via syringe. The reaction mixturewas purged with N₂ for about 10 min and stirred under an atmosphere ofN₂ at about 70° C. for about 3 h. The reaction mixture was allowed tocool to ambient temperature. The solvent was removed under reducedpressure. The residue was purified by silica gel flash chromatographyeluting with a gradient of 5-70% EtOAc in heptane to yield1-(4-(dibenzylamino)cyclohexyl)-2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)ethanone(5.8 g, 65%) as glassy solid: LC/MS (Table 1, Method a) R_(t)=3.24 and3.26 min; MS m/z 608 (M+H)⁺.

Example #1 Example #1.1N,N-diethyl-1-((1S,3R,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methanesulfonamideExample #1.2N,N-diethyl-1-((1R,3S,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methanesulfonamideExample #1.3N,N-diethyl-1-((1S,3S,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methanesulfonamideExample #1.4N,N-diethyl-1-((1R,3R,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methanesulfonamideExample #1.5N,N-diethyl-1-((1S,3S,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methanesulfonamide,and Example #1.6N,N-diethyl-1-((1R,3S,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methanesulfonamide

Step A: 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine

To a solution of 3,5-dibromopyrazin-2-amine (125 g, 494 mmol), TEA(207.0 mL, 1483 mmol), and copper (I) iodide (0.941 g, 4.94 mmol) in THF(1255 mL) was added PdCl₂(PPh₃)₂ (3.47 g, 4.94 mmol). The reactionmixture was cooled at about −5-0° C. and a solution of(trimethylsilyl)acetylene (65.0 mL, 470 mmol) in THF (157 mL) was addeddropwise over about 15 min. The reaction mixture was stirred at about−5-0° C. for about 1.5 h and then allowed to warm to rt overnight. Thereaction mixture was then filtered through a Celite® pad and washed withTHF until no further product eluted. The filtrate was concd underreduced pressure to give a brown-orange solid. The solid was trituratedand sonicated with warm petroleum ether (b.p. 30-60° C., 400 mL), cooledto rt, collected, washed with petroleum ether (b.p. 30-60° C.; 2×60 mL),and dried to give 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine(124 g, 93%, 93% purity) as a brown solid: LC/MS (Table 1, Method b)R_(t)=2.51 min; MS m/z: 270, 272 (M+H)⁺.

Step B: 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine

To a solution of 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine(3.00 g, 11.1 mmol) in DMF (60 mL) at about 0° C. was added NaH (60%dispersion in mineral oil, 0.577 g, 14.4 mmol) in three portions. Afterabout 15 min, p-toluenesulfonyl chloride (2.75 g, 14.4 mmol) was addedand the reaction was allowed to warm slowly to ambient temperature.After about 16 h, the reaction mixture was poured onto ice-cold water(120 mL) and the precipitate was collected by vacuum filtration. Thecrude solid was dissolved in DCM (15 mL) and purified by silica gelchromatography eluting with DCM to give2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (2.16 g, 52%): LC/MS (Table 1,Method c) R_(t)=1.58 min; MS m/z: 352, 354 (M+H)⁺.

Step C: tert-butyl2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate andtert-butyl 1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate

To a flask was added Pd₂(dba)₃ (3.90 g, 4.26 mmol),di-tert-butyl-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphane (3.62 g,8.52 mmol), and 1,4-dioxane (453 mL). The catalyst-ligand mixture wasdegassed via vacuum/nitrogen purge (3 times) and heated at about 80° C.for about 10 min and cooled to ambient temperature. Then2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (30.0 g, 85 mmol), tert-butylhydrazinecarboxylate (16.9 g, 128 mmol), and NaOt-Bu (12.28 g, 128 mmol)were added. After an additional vacuum/nitrogen purge, the reaction washeated at about 80° C. After about 50 min, the reaction mixture wascooled to ambient temperature and filtered through a pad of silica gel(6 cm in height×6 cm in diameter), topped with Celite® (1 cm in height×6cm in diameter), while washing with EtOAc (3×150 mL). Water (300 mL) wasadded to the filtrate and the organic layer was separated. The aqueouslayer was extracted with additional EtOAc (3×200 mL). The combinedorganic extracts were washed with saturated aqueous NH₄Cl, saturatedaqueous NaHCO₃, and brine (400 mL each), dried over anhydrous MgSO₄,filtered, and concd under reduced pressure to give a dark brown oil (45g). The brown oil was dissolved in DCM (250 mL), silica gel (200 g) wasadded, and the mixture was concd under reduced pressure. The resultingsilica mixture was purified using silica gel chromatography eluting witha gradient of 25-65% EtOAc in heptane to give a mixture of tert-butyl2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate [majorregioisomer] and tert-butyl1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate [minorregioisomer] (18.8 g, 50%): LC/MS (Table 1, Method c) R_(t)=1.47 min; MSm/z: 404 (M+H)⁺.

Step D: 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine

To a mixture of tert-butyl2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate andtert-butyl 1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate(49.2 g, 122 mmol) in 1,4-dioxane (290 mL) was added HCl (4 M in1,4-dioxane, 226 mL, 902 mmol). The reaction was heated at about 60° C.for about 2.5 h and then cooled to about 15-20° C. The solid wascollected by vacuum filtration, washed with EtOAc (3×50 mL), and thentriturated with Et₂O (60 mL), collected by vacuum filtration and driedto a constant weight under vacuum to yield 35.6 g of solid. The solidwas stirred with a mixture of saturated aqueous NaHCO₃ and EtOAc (1:1,400 mL). After about 1 h, the solid was collected by vacuum filtration,washed with ice cold water (3×30 mL) and EtOAc (3×30 mL), and dried in avacuum oven to a constant weight to afford2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine as a tan solid (21.2 g,57%): LC/MS (Table 1, Method a) R_(t)=1.88 min; MS m/z: 304 (M+H)⁺.

Step E: sodium4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-dienolate

A round bottom flask was charged with THF (1.5 L) followed by theportionwise addition of NaH (60% dispersion in mineral oil, 70.0 g, 1.75mol). Additional THF (500 mL) was added and the resulting mixture wascooled to about −10° C. and ethyl propionylacetate (250 mL, 1.80 mol)was added dropwise over about 1 h in order to keep internal temperaturebelow about 10° C. The resulting mixture was stirred at ambienttemperature for about 0.5 h to give a clear yellow solution, and methyl4-chloroacetoacetate (100 mL, 0.88 mol) was added dropwise over about 5min. The resulting mixture was heated at about 50° C. for about 19 h togive a reddish orange suspension. The reaction mixture was cooled toambient temperature, concd under reduced pressure and the resultingliquid was transferred to a beaker and diluted with water (350 mL). Themixture was stirred in an ice bath for about 2 h. The solid wascollected by vacuum filtration and the filter cake was rinsed with water(150 mL) and dried under vacuum for about 1 h. The solid was suspendedin Et₂O (1.5 L), filtered, washed with Et₂O (1.5 L), and dried undervacuum. The resulting solid was azeotroped with toluene (1 L) to give asolid that was re-suspended in Et₂O (1 L) and collected by vacuumfiltration. The filter cake was washed with Et₂O (500 mL) and driedunder vacuum to give sodium4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-dienolate(204.2 g, 89%) as beige solid: ¹H NMR (DMSO-d₆) δ 3.94 (q, J=7.1 Hz,2H), 3.46 (s, 3H), 3.04 (q, J=7.2 Hz, 2H), 2.66 (s, 2H), 1.13 (t, J=7.1Hz, 3H), 0.99 (t, J=7.3 Hz, 3H).

Step F: ethyl 2-ethyl-4-oxocyclopent-2-enecarboxylate

A 5 liter round bottom flask was charged with sodium4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-dienolate(316 g, 1205 mmol), KCl (126 g, 1687 mmol, JT-Baker), AcOH (241 mL, 4218mmol, JT-Baker), toluene (1850 mL) and water (130 mL). The reaction washeated at reflux for about 6 h then cooled to ambient temperature andadded dropwise to NaHCO₃ (8% aqueous, 3.5 L). The resulting biphasicmixture was extracted with MTBE (2×1.5 L). The combined organic layerswere washed with brine (1 L), dried over anhydrous MgSO₄ and concd underreduced pressure to give 191 g of crude material that was purified byvacuum distillation (97-99° C., 0.600 mm Hg) to give ethyl2-ethyl-4-oxocyclopent-2-enecarboxylate (160 g, 69%): ¹H NMR (CDCl₃) δ6.04 (m, 1H), 4.26-4.15 (m, 2H), 3.76-3.69 (m, 1H), 2.75-2.57 (m, 2H),2.56-2.44 (m, 2H), 1.32-1.26 (m, 3H), 1.23-1.18 (m, 3H).

Step G: ethyl 2-ethyl-4-oxocyclopentanecarboxylate

A round bottom flask was charged with 10 wt % Pd/C (10 g, 9.4 mmol). Theflask was cooled to about 0° C. and EtOAc (400 mL) was added under anitrogen atmosphere. The cooling bath was removed and ethyl2-ethyl-4-oxocyclopent-2-enecarboxylate (47.8 g, 263 mmol) was added.Hydrogen gas was bubbled through the mixture for about 5 min and themixture was then stirred under a hydrogen atmosphere for about 48 h. Thehydrogen source was removed and the mixture was bubbled with nitrogenfor about 5 min and was filtered through a pad of Celite®. The filtercake was rinsed with EtOAc (400 mL). The filtrate was concd underreduced pressure to give ethyl 2-ethyl-4-oxocyclopentanecarboxylate(about 9:1 mixture cis: trans) (48.0 g, 99%) as a yellow liquid: ¹H NMR(CDCl₃) δ 4.23-4.10 (m, 2H), 3.22 (m, 1H), 2.59-2.50 (m, 1H), 2.44-2.28(m, 3H), 2.26-2.16 (m, 1H), 1.58-1.46 (m, 1H), 1.41-1.30 (m, 1H),1.30-1.23 (m, 3H), 1.02-0.91 (m, 3H).

Step H: ethyl 2-ethyl-4-methylenecyclopentanecarboxylate

A solution of KOt-Bu (3.65 g, 32.6 mmol) and methyltriphenylphosphoniumbromide (11.6 g, 32.6 mmol) in THF (69.5 mL) was cooled to about −10° C.A solution of ethyl 2-ethyl-4-oxocyclopentanecarboxylate (4.00 g, 21.7mmol) in THF (17.4 mL) was added dropwise while the temperature was keptat about 0° C. The reaction mixture was allowed to warm to ambienttemperature and stirred for about 16 h. The insoluble material wasremoved by filtration. The filtrate was concd under reduced pressure.The resulting material was purified by silica gel (120 g) chromatographyeluting with a gradient of 0-20% EtOAc in heptane to provide ethyl2-ethyl-4-methylenecyclopentanecarboxylate (2.55 g, 64%) as a colorlessliquid: ¹H NMR (d-DMSO) δ 4.88-4.78 (m, 2H), 4.16-3.96 (m, 2H),2.66-2.31 (m, 4H), 2.24-1.82 (m, 2H), 1.50 (m, 1H), 1.35-1.22 (m, 1H),1.18 (t, 3H), 0.85 (m, 3H).

Step I: ethyl 2-ethyl-4-(mercaptomethyl)cyclopentanecarboxylate

Ethyl 2-ethyl-4-methylenecyclopentanecarboxylate (0.720 g, 3.95 mmol),triphenylsilanethiol (1.329 g, 4.54 mmol) and2,2′-azobis(2-methylpropionitrile) (0.195 g, 1.185 mmol) in toluene(3.95 mL) was heated at reflux for about 6 h. The reaction mixture wascooled to ambient temperature and then concd under reduced pressure. Thematerial was purified by silica gel (40 g) chromatography eluting with agradient of 0-10% EtOAc in heptane to give a colorless oil. Theresulting oil was dissolved in DCM (4 mL) and TFA (1.52 mL, 19.7 mmol)was added. After stirring at ambient temperature for about 1 h, thesolvent was removed under reduced pressure. The material was purified bysilica gel (40 g) chromatography eluting with a gradient of 0-15% EtOAcin heptane to provide ethyl2-ethyl-4-(mercaptomethyl)cyclopentanecarboxylate (0.620 g, 72%) as acolorless oil: ¹H NMR (DMSO-d₆) δ 4.13-4.01 (m, 2H), 2.50-2.30 (m, 3H),2.24 (m, 1H), 2.15-1.87 (m, 3H), 1.66-1.54 (m, 1H), 1.50-1.37 (m, 2H),1.31-1.23 (m, 2H), 1.17 (t, 3H), 0.83 (m, 3H).

Step J: (3-(ethoxycarbonyl)-4-ethylcyclopentyl)methanesulfonic acid

To a stirred solution of ethyl2-ethyl-4-(mercaptomethyl)cyclopentanecarboxylate (2.50 g, 11.6 mmol) inDCM (50.7 mL) was added dropwise ethaneperoxoic acid (7.29 mL, 34.7mmol) at about 0° C. The reaction mixture was warmed to ambienttemperature and stirred for about 16 h. The solution was concd underreduced pressure to yield crude(3-(ethoxycarbonyl)-4-ethylcyclopentyl)methanesulfonic acid (3.18 g,104%) as a dark brown oil: LC/MS (Table 1, Method b) R_(t)=1.39 min; MSm/z: 265 (M+H)⁺.

Step K: ethyl4-((N,N-diethylsulfamoyl)methyl)-2-ethylcyclopentanecarboxylate

A solution of (3-(ethoxycarbonyl)-4-ethylcyclopentyl)methanesulfonicacid (3.18 g, 12.03 mmol) in DCM (10 mL) and DMF (10 mL) was cooled toabout 0° C. Oxalyl chloride (24.1 mL, 48.1 mmol) was added dropwisewhile the temperature was kept at about 0° C. After the addition wascomplete, the reaction mixture was warmed to ambient temperature andstirred for about 1 h. The solvent was removed under reduced pressure.The residue was dissolved in DMF (10 mL) and then added dropwise to asolution of TEA (2.51 mL, 18.03 mmol) and diethylamine (0.937 mL, 9.02mmol) in DMF (10 mL) at about 0° C. The reaction mixture was stirred atambient temperature for about 16 h. The solvent was removed underreduced pressure. The material was purified by silica gel (120 g)chromatography eluting with a gradient of 10-60% EtOAc in heptane toprovide ethyl4-((N,N-diethylsulfamoyl)methyl)-2-ethylcyclopentanecarboxylate (0.570g, 30%) as a yellow oil: LC/MS (Table 1, Method b) R_(t)=2.60 min; MSm/z: 320 (M+H)⁺.

Step L: 4-((N,N-diethylsulfamoyl)methyl)-2-ethylcyclopentanecarboxylicacid

A mixture of ethyl4-((N,N-diethylsulfamoyl)methyl)-2-ethylcyclopentanecarboxylate (0.570g, 1.784 mmol) in NaOH (1 N aqueous, 10 mL, 10 mmol) was stirred atambient temperature for about 72 h. The mixture was partitioned with DCM(10 mL). The aqueous phase was acidified to about pH=4 by addition of 6N aqueous HCl. The solution was partitioned with DCM (10 mL). Theaqueous phase was washed with DCM (2×10 mL). The organic layers werecombined, dried over anhydrous MgSO₄, and concd under reduced pressureto give 4-((N,N-diethylsulfamoyl)methyl)-2-ethylcyclopentanecarboxylicacid (0.375 g, 72%) as yellow oil: LC/MS (Table 1, Method b) R_(t)=1.95min; MS m/z: 292 (M+H)⁺.

Step M:N,N-diethyl-1-(3-ethyl-4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclopentyl)methanesulfonamide

To a suspension of 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (0.390g, 1.287 mmol, Example #1 Step D),4-((N,N-diethylsulfamoyl)methyl)-2-ethylcyclopentanecarboxylic acid(0.375 g, 1.287 mmol), and HATU (0.538 g, 1.416 mmol) in DCM (6.4 mL)was added TEA (0.538 mL, 3.86 mmol). The reaction mixture was stirred atambient temperature for about 1 h. The reaction mixture was partitionedbetween water (50 mL) and DCM (50 mL). The aqueous layer was extractedwith DCM (2×50 mL). The organic layers were combined and concd underreduced pressure. The material was purified by silica gel (120 g)chromatography eluting with a gradient of 20-100% EtOAc in DCM toprovideN,N-diethyl-1-(3-ethyl-4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclopentyl)methanesulfonamide(0.730 g, 98%) as a brown solid: LC/MS (Table 1, Method b) R_(t)=2.39min; MS m/z: 577 (M+H)⁺.

Step N:N,N-diethyl-1-(3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methanesulfonamide

To a mixture ofN,N-diethyl-1-(3-ethyl-4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclopentyl)methanesulfonamide(0.730 g, 1.27 mmol) and TEA (0.529 mL, 3.80 mmol) in 1,4-dioxane (12.7mL) was added SOCl₂ (0.185 mL, 2.53 mmol). The reaction mixture washeated at about 80° C. for about 2 h. The reaction mixture was cooled toambient temperature and partitioned between saturated aqueous NaHCO₃ (30mL) and DCM (30 mL). The aqueous layer was washed with DCM (2×30 mL).The organic layers were combined, concd under reduced pressure, andpurified by silica gel (80 g) chromatography eluting with a gradient of0-60% MeOH in DCM to give a brown solid. The resulting solid wassuspended in Na₂CO₃ (2 M aqueous, 2 mL), EtOH (2 mL) and 1,4-dioxane (2mL). The reaction mixture was heated at about 60° C. for about 16 h. Thereaction mixture was cooled to ambient temperature and purified byRP-HPLC (Table 1, Method d) to affordN,N-diethyl-1-(3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methanesulfonamide(0.300 g, 58%) as a tan solid: LC/MS (Table 1, Method b) R_(t)=1.89 min;MS m/z: 405 (M+H)⁺. The solid was further purified by using GeneralProcedure AA to giveN,N-diethyl-1-((1S,3R,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methanesulfonamide(Table 2, Method 27, R_(t)=11.8 min, or =negative) (0.021 g, 7%)[Example #1.1];N,N-diethyl-1-((1R,3S,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methane-sulfonamide(Table 2, Method 27, R_(t)=11.1 min, or =positive) (0.018 g, 6%)[Example #1.2];N,N-diethyl-1-((1S,3S,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclo-pentyl)methanesulfonamide(Table 2, Method 27, R_(t)=10.7 min, or =positive) (0.018 g, 6%)[Example #1.3];N,N-diethyl-1-((1R,3R,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methanesulfonamide(Table 2, Method 28, R_(t)=20.1 min, or =negative) (0.031 g, 11%)[Example #1.4];N,N-diethyl-1-((1S,3S,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methanesulfonamide(Table 2, Method 27, R_(t)=12.8 min, or =positive) (0.002 g, 1%)[Example #1.5]; andN,N-diethyl-1-((1R,3S,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methanesulfonamide(Table 2, Method 27, R_(t)=12.8 min, or =positive) (0.001 g, 1%)[Example #1.6].

Example #2*N-((1R,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)aniline

Step A: 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine

To a solution of 3,5-dibromopyrazin-2-amine (125 g, 494 mmol), TEA(207.0 mL, 1483 mmol), and copper (I) iodide (0.941 g, 4.94 mmol) in THF(1255 mL) was added PdCl₂(PPh₃)₂ (3.47 g, 4.94 mmol). The reactionmixture was cooled at about −5-0° C. and a solution of(trimethylsilyl)acetylene (65.0 mL, 470 mmol) in THF (157 mL) was addeddropwise over about 15 min. The reaction mixture was stirred at about−5-0° C. for about 1.5 h and then allowed to warm to rt overnight. Thereaction mixture was then filtered through a Celite® pad and washed withTHF until no further product eluted. The filtrate was concd underreduced pressure to give a brown-orange solid. The solid was trituratedand sonicated with warm petroleum ether (b.p. 30-60° C., 400 mL), cooledto rt, collected, washed with petroleum ether (b.p. 30-60° C.; 2×60 mL),and dried to give 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine(124 g, 93%, 93% purity) as a brown solid: LC/MS (Table 1, Method b)R_(t)=2.51 min; MS m/z: 270, 272 (M+H)⁺.

Step B: 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine

To a solution of 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine(3.00 g, 11.1 mmol) in DMF (60 mL) at about 0° C. was added NaH (60%dispersion in mineral oil, 0.577 g, 14.4 mmol) in three portions. Afterabout 15 min, p-toluenesulfonyl chloride (2.75 g, 14.4 mmol) was addedand the reaction was allowed to warm slowly to ambient temperature.After about 16 h, the reaction mixture was poured onto ice-cold water(120 mL) and the precipitate was collected by vacuum filtration. Thecrude solid was dissolved in DCM (15 mL) and purified by silica gelchromatography eluting with DCM to give2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (2.16 g, 52%): LC/MS (Table 1,Method c) R_(t)=1.58 min; MS m/z: 352, 354 (M+H)⁺.

Step C: tert-butyl2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate andtert-butyl 1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate

To a flask was added Pd₂(dba)₃ (3.90 g, 4.26 mmol),di-tert-butyl-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphane (3.62 g,8.52 mmol), and 1,4-dioxane (453 mL). The catalyst-ligand mixture wasdegassed via vacuum/nitrogen purge (3 times) and heated at about 80° C.for about 10 min. Then 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (30.0g, 85 mmol), tert-butyl hydrazinecarboxylate (16.9 g, 128 mmol), andNaOt-Bu (12.28 g, 128 mmol) were added. After an additionalvacuum/nitrogen purge, the reaction was heated at about 80° C. Afterabout 50 min, the reaction mixture was cooled to ambient temperature andfiltered through a pad of silica gel (6 cm in height×6 cm in diameter),topped with Celite® (1 cm in height×6 cm in diameter), while washingwith EtOAc (3×150 mL). Water (300 mL) was added to the filtrate and theorganic layer was separated. The aqueous layer was extracted withadditional EtOAc (3×200 mL). The combined organic extracts were washedwith saturated aqueous NH₄Cl, saturated aqueous NaHCO₃, and brine (400mL each), dried over anhydrous MgSO₄, filtered, and concd under reducedpressure to give a dark brown oil (45 g). The brown oil was dissolved inDCM (250 mL), silica gel (200 g) was added, and the mixture was concdunder reduced pressure. The resulting silica mixture was purified usingsilica gel chromatography eluting with a gradient of 25-65% EtOAc inheptane to give a mixture of tert-butyl2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate [majorregioisomer] and tert-butyl1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate [minorregioisomer] (18.8 g, 50%): LC/MS (Table 1, Method c) R_(t)=1.47 min; MSm/z: 404 (M+H)⁺.

Step D: 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine

To a mixture of tert-butyl2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate andtert-butyl 1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate(49.2 g, 122 mmol) in 1,4-dioxane (290 mL) was added HCl (4 M in1,4-dioxane, 226 mL, 902 mmol). The reaction was heated at about 60° C.for about 2.5 h and then cooled to about 15-20° C. The solid wascollected by vacuum filtration, washed with EtOAc (3×50 mL), and thentriturated with Et₂O (60 mL), collected by vacuum filtration and driedto a constant weight under vacuum to yield 35.6 g of solid. The solidwas stirred with a mixture of saturated aqueous NaHCO₃ and EtOAc (1:1,400 mL). After about 1 h, the solid was collected by vacuum filtration,washed with ice cold water (3×30 mL) and EtOAc (3×30 mL), and dried in avacuum oven to a constant weight to afford2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine as a tan solid (21.2 g,57%): LC/MS (Table 1, Method a) R_(t)=1.88 min; MS m/z: 304 (M+H)⁺.

Step E: tert-butyl(1R,3R)-3-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclopentylcarbamate

To (1R,3R)-3-(tert-butoxycarbonylamino)cyclopentanecarboxylic acid (2.25g, 9.81 mmol, Acros) in DCM (98 mL) was added2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (2.98 g, 9.81 mmol), HATU(3.73 g, 9.81 mmol) and TEA (5.5 mL, 39 mmol). The reaction mixture wasstirred at ambient temperature for about 4 h then diluted with DCM (300mL). The reaction mixture was washed with water (2×80 mL), saturatedaqueous NaHCO₃ (80 mL), dried over anhydrous MgSO₄, filtered, and concdunder reduced pressure. The residue was purified using silica gelchromatography (220 g) eluting with a gradient of 50-100% EtOAc in DCMgive tert-butyl(1R,3R)-3-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclopentylcarbamate(5.03 g, 100%) as a brown solid: LC/MS (Table 1, Method b) R_(t)=2.18min; MS m/z: 513 (M−H)⁻

Step F:(1R,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine

To tert-butyl(1R,3R)-3-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclo-pentylcarbamate(5.03 g, 9.78 mmol) in 1,4-dioxane (103 mL) was added DIEA (7.2 mL, 41mmol) and SOCl₂ (2.3 mL, 31 mmol). The reaction mixture was heated atabout 80° C. for about 1 h. The solvent was removed under reducedpressure and the residue was purified using silica gel chromatography(330 g) eluting with a gradient of 0-20% MeOH in DCM to give(1R,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine(2.65 g, 68%): LC/MS (Table 1, Method b) R_(t)=1.55 min; MS m/z: 397(M+H)⁺.

Step G:N-((1R,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)aniline

A 100 mL round bottom flask was sequentially charged with phenylboronicacid (0.123 g, 1.01 mmol), diacetoxycopper monohydrate (0.010 g, 0.05mmol), powdered 4 Å molecular sieves (0.375 g) and DCM (4 mL). Thereaction mixture was stirred for about 10 min then a suspension of(1R,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine(0.20 g, 0.50 mmol) in DCM (2 mL) and MeCN (2 mL) was added. The flaskwas fitted with an oxygen balloon. The flask was purged with oxygen andthen heated at about 40° C. for about 18 h. Additional diacetoxycoppermonohydrate (0.010 g, 0.05 mmol) was added and the reaction mixture washeated at about 45° C. under an atmosphere of oxygen for about 3 days.DCM (50 mL) was added and the reaction mixture was filtered through apad of Celite® while washing with DCM (20 mL). The filtrate was concdunder reduced pressure and the residue was purified using silica gelchromatography (20 g) eluting with a gradient of 30-80% EtOAc in DCM togiveN-((1R,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)aniline(0.106 g, 45%): LC/MS (Table 1, Method b) R_(t)=2.39 min; MS m/z: 473(M+H)⁺.

Step H:N-((1R,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)aniline

ToN-((1R,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)aniline(0.106 g, 0.224 mmol) in 1,4-dioxane (1 mL) was added NaOH (1 N aqueous,1.12 mL, 1.12 mmol). The reaction mixture was heated at about 60° C. forabout 1 h. AcOH (0.5 mL) was added and the crude reaction mixture waspurified by RP-HPLC (Table 1, Method j) to giveN-((1R,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)aniline(0.053 g, 74%) as a light yellow solid: LC/MS (Table 1, Method b)R_(t)=1.84 min; MS m/z: 319 (M+H)⁺.

Example #3*(R)-(3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidin-1-yl)(3,3-difluorocyclobutyl)methanone

Step A: 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine

To a solution of 3,5-dibromopyrazin-2-amine (125 g, 494 mmol), TEA(207.0 mL, 1483 mmol), and copper (I) iodide (0.941 g, 4.94 mmol) in THF(1255 mL) was added PdCl₂(PPh₃)₂ (3.47 g, 4.94 mmol). The reactionmixture was cooled at about −5-0° C. and a solution of(trimethylsilyl)acetylene (65.0 mL, 470 mmol) in THF (157 mL) was addeddropwise over about 15 min. The reaction mixture was stirred at about−5-0° C. for about 1.5 h and then allowed to warm to rt overnight. Thereaction mixture was then filtered through a Celite® pad and washed withTHF until no further product eluted. The filtrate was concd underreduced pressure to give a brown-orange solid. The solid was trituratedand sonicated with warm petroleum ether (b.p. 30-60° C., 400 mL), cooledto rt, collected, washed with petroleum ether (b.p. 30-60° C.; 2×60 mL),and dried to give 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine(124 g, 93%, 93% purity) as a brown solid: LC/MS (Table 1, Method b)R_(t)=2.51 min; MS m/z: 270, 272 (M+H)⁺.

Step B: 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine

To a solution of 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine(3.00 g, 11.1 mmol) in DMF (60 mL) at about 0° C. was added NaH (60%dispersion in mineral oil, 0.577 g, 14.4 mmol) in three portions. Afterabout 15 min, p-toluenesulfonyl chloride (2.75 g, 14.4 mmol) was addedand the reaction was allowed to warm slowly to ambient temperature.After about 16 h, the reaction mixture was poured onto ice-cold water(120 mL) and the precipitate was collected by vacuum filtration. Thecrude solid was dissolved in DCM (15 mL) and purified by silica gelchromatography eluting with DCM to give2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (2.16 g, 52%): LC/MS (Table 1,Method c) R_(t)=1.58 min; MS m/z: 352, 354 (M+H)⁺.

Step C: methyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylate

CO was bubbled into an orange solution of2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (50.0 g, 142 mmol) in DMF(2.50 L) within a 5 L round bottom flask for about 2 min.Bis(triphenylphosphine)-palladium(II) dichloride (9.96 g, 14.2 mmol),TEA (59 mL, 423 mmol) and MeOH (173.0 mL, 4259 mmol) were added and theflask was fitted with a balloon of CO. The mixture was heated at about95° C. under an atmosphere of CO (1 atmosphere). After stirringovernight, the reaction mixture was cooled to ambient temperatureovernight and poured into ice water (3.2 L). The mixture was stirred forabout 10 min and the precipitate was collected by filtration, whilewashing with water, and dried for 1 h. The crude material was dissolvedin DCM, separated from residual water, dried over anhydrous MgSO₄,filtered, added silica gel, and concd under reduced pressure to preparefor chromatography. The crude material was purified by silica gel columnchromatography eluting with 0-5% MeOH in DCM to yield methyl5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylate with 5 mol % DCM as anexcipient (40.7 g, 86%, 93% purity): LC/MS (Table 1, Method a)R_(t)=2.35 min; MS m/z 332 (M+H)⁺.

Step D: 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylic acid

HCl (6 N aqueous, 714 mL) was added to a yellow solution of methyl5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylate (17.8 g, 53.6 mmol) in1,4-dioxane (715 mL) within a 2 L round bottom flask, and the mixturewas heated at about 60° C. for about 16 h. The reaction mixture wascooled to ambient temperature. The organic solvent was removed underreduced pressure and the precipitate was collected, washed with water,and dried to yield 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylic acid(14.4 g, 85%) as a yellow solid: LC/MS (Table 1, Method a) R_(t)=1.63min; MS m/z 316 (M−H)⁻.

Step E: tert-butyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate

In a 500 mL round bottom flask,5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylic acid (14.4 g, 45.3 mmol),diphenylphosphoryl azide (9.78 mL, 45.3 mmol) and TEA (13.9 mL, 100mmol) in t-BuOH (200 mL) were added to give an orange suspension. Themixture was heated at about 70° C. for about 16 h, cooled to ambienttemperature and the insoluble material was removed by filtration. Thesolvent was removed under reduced pressure and the crude material waspurified by silica gel column chromatography eluting with 25-60% EtOAcin heptane to yield tert-butyl5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (9.75 g, 54%) as anoff-white solid: LC/MS (Table 1, Method a) R_(t)=2.79 min; MS m/z 389(M+H)⁺.

Step F: (R)-1-(benzyloxycarbonyl)piperidine-3-carboxylic acid

A mixture of (R)-piperidine-3-carboxylic acid (3.0 g, 23 mmol), benzyl2,5-dioxopyrrolidin-1-yl carbonate (5.79 g, 23.2 mmol) and Na₂CO₃ (6.15g, 58.1 mmol) was stirred in water and 1,4-dioxane (1:1, 200 mL) atambient temperature for about 96 h. The organic solvent was removedunder reduced pressure. The aqueous layer was acidified with 1 N aqueousHCl and extracted with EtOAc (2×100 mL). The organic phase was washedwith brine (150 mL), dried over anhydrous MgSO₄ and concd under reducedpressure to yield crude(R)-1-(benzyloxycarbonyl)-piperidine-3-carboxylic acid (11.6 g, 191%) asa white solid: LC/MS (Table 1, Method a) R_(t)=1.80 min; MS m/z 264(M+H)⁺.

Step G: (R)-8-(piperidin-3-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazinehydrobromide and(S)-8-(piperidin-3-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazinehydrobromide

Oxalyl chloride (8.41 mL, 96 mmol) was added to a solution of(R)-1-(benzyloxycarbonyl)piperidine-3-carboxylic acid (11.5 g, 43.7mmol, Ex#3, step F) in DCM (120 mL) followed by a dropwise addition ofDMF (0.5 mL, 6.55 mmol). The resulting mixture was stirred at ambienttemperature for about 14 h. The solvent was removed under reducedpressure to yield a crude acid chloride (Ex#3 G1) as a yellowsemi-solid, which was dissolved in THF and MeCN (1:1, 160 mL) and addedto trimethylsilyldiazomethane (2 M in Et₂O, 78 mL, 155 mmol) in THF andMeCN (1:1, 160 mL) at about 0° C. The reaction mixture was stirred atabout 0° C. for about 2 h after the completion of the addition. Thereaction mixture was then quenched by a dropwise addition of HBr (48%aqueous, 40 mL, 354 mmol). The organic solvents were removed underreduced pressure and the residue dissolved in EtOAc (100 mL). Theorganic phase was washed with saturated aqueous NaHCO₃ (100 mL), andbrine (25 mL), dried over anhydrous MgSO₄, filtered, and concd underreduced pressure. The residue was purified by silica gel chromatographyeluting with 5 to 45% EtOAc in heptane to yield the crude benzyl3-(2-bromoacetyl)piperidine-1-carboxylate (Ex#3 G2) as a colorless oil.To a mixture of NaH (60% dispersion in mineral oil, 0.55 g, 14 mmol) inDMF (20 mL) was added dropwise a solution of tert-butyl5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (Ex#3 step F) (5.00 g,12.9 mmol) in DMF (20 mL) at about 0° C. The reaction mixture wasstirred at this temperature for about 30 min and was then added dropwiseto a solution of crude benzyl 3(2-bromoacetyl)piperidine-1-carboxylate(Ex#3 G2) (5.26 g, 15.5 mmol) in DMF (40 mL) at about 0° C. The mixturewas stirred for about 3 h while warming to ambient temperature. Thesolvent was removed under reduced pressure and the residue partitionedbetween saturated aqueous NH₄Cl and EtOAc (70 mL each). The organicphase was further washed with brine (60 mL), dried over anhydrous MgSO₄,filtered, and concd under reduced pressure to yield crude Boc-protectedaminomethylketone (Ex#3 G3) as a yellow oil that was used in the nextstep without further purification. The oil was dissolved in HCl (4 N in1,4-dioxane, 40 mL) and the solution was stirred at ambient temperaturefor about 2 h. The solvent was removed under reduced pressure and theresidue partitioned between saturated aqueous NaHCO₃ and DCM (200 mLeach). The organic phase was washed with brine (150 mL), dried overanhydrous MgSO₄, filtered, and concd under reduced pressure to yieldcrude aminomethylketone (Ex#3 G4) as a brown amorphous solid. It wasdissolved in 1,4-dioxane (100 mL) and Lawesson's reagent (1.94 g, 4.80mmol) was added. The reaction mixture was heated at about 60° C. forabout 2 h. NaOH (2 N aqueous, 3 mL) was added and heating was continuedat about 90° C. for about 4 h. The organic solvent was removed underreduced pressure and saturated aqueous NH₄Cl (120 mL) was added. Theaqueous phase was extracted with DCM (2×100 mL) and the combined organicextracts were dried over anhydrous MgSO₄, filtered, and concd underreduced pressure. The crude material was purified by silica gel columnchromatography eluting with 0-10% MeOH in DCM to yield crudeimidazo[1,2-a]pyrrolo[2,3-e]pyrazine (Ex#3 G5) as a yellow amorphoussolid. It was suspended in HBr (33% in AcOH, 10 mL). The resultingmixture was stirred for about 10 min and then was diluted with EtOAc (80mL). The precipitate was collected by filtration and exhaustively washedwith EtOAc to yield(R)-8-(piperidin-3-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazinehydrobromide and(S)-8-(piperidin-3-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazinehydrobromide [er=80:20] (2.61 g, 62.9% overall) as a yellow solid: LC/MS(Table 1, Method a) R_(t)=0.63 min; MS m/z 242 (M+H); chiral analyticalLC (Table 1, Method 29) R_(t)=17.75 min, or =negative and R_(t)=20.33min, or =positive.

Step H:(R)-(3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidin-1-yl)(3,3-difluorocyclobutyl)methanone

To a solution of(R)-8-(piperidin-3-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazinehydrobromide and(S)-8-(piperidin-3-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazinehydrobromide [er=80:20] (0.30 g, 0.93 mmol), DIEA (0.52 mL, 3.0 mmol)and 3,3-difluorocyclobutanecarboxylic acid (0.35 g, 3.1 mmol,Waterstone) in DMF (4 mL) was added EDC.HCl (0.21 g, 1.1 mmol). Thereaction was stirred at about 25° C. for about 4 h. The reaction waspartitioned with aqueous Na₂CO₃ (2 M, 25 mL) and DCM (25 mL). Theorganic layer was separated, dried over anhydrous Na₂SO₄, filtered, andconcd in vacuo. The resulting residue was purified on silica gel (12 g)using 0-5% MeOH in DCM followed by purification using General ProcedureAA (Table 2, Method 23, R_(t)=16.4 min, or =positive) to give(R)-(3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidin-1-yl)(3,3-difluorocyclobutyl)-methanone(0.10 g, 30%): LC/MS (Table 1, Method b) R_(t)=1.85 min; MS m/z: 360(M+H)⁺.

Example #4*4-((1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyloxy)benzonitrile

Step A: 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine

To a solution of 3,5-dibromopyrazin-2-amine (125 g, 494 mmol), TEA(207.0 mL, 1483 mmol), and copper (I) iodide (0.941 g, 4.94 mmol) in THF(1255 mL) was added PdCl₂(PPh₃)₂ (3.47 g, 4.94 mmol). The reactionmixture was cooled at about −5-0° C. and a solution of(trimethylsilyl)acetylene (65.0 mL, 470 mmol) in THF (157 mL) was addeddropwise over about 15 min. The reaction mixture was stirred at about−5-0° C. for about 1.5 h and then allowed to warm to rt overnight. Thereaction mixture was then filtered through a Celite® pad and washed withTHF until no further product eluted. The filtrate was concd underreduced pressure to give a brown-orange solid. The solid was trituratedand sonicated with warm petroleum ether (b.p. 30-60° C., 400 mL), cooledto rt, collected, washed with petroleum ether (b.p. 30-60° C.; 2×60 mL),and dried to give 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine(124 g, 93%, 93% purity) as a brown solid: LC/MS (Table 1, Method b)R_(t)=2.51 min; MS m/z: 270, 272 (M+H)⁺.

Step B: 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine

To a solution of 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine(3.00 g, 11.1 mmol) in DMF (60 mL) at about 0° C. was added NaH (60%dispersion in mineral oil, 0.577 g, 14.4 mmol) in three portions. Afterabout 15 min, p-toluenesulfonyl chloride (2.75 g, 14.4 mmol) was addedand the reaction was allowed to warm slowly to ambient temperature.After about 16 h, the reaction mixture was poured onto ice-cold water(120 mL) and the precipitate was collected by vacuum filtration. Thecrude solid was dissolved in DCM (15 mL) and purified by silica gelchromatography eluting with DCM to give2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (2.16 g, 52%): LC/MS (Table 1,Method c) R_(t)=1.58 min; MS m/z: 352, 354 (M+H)⁺.

Step C: tert-butyl2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate andtert-butyl 1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate

To a flask was added Pd₂(dba)₃ (3.90 g, 4.26 mmol),di-tert-butyl-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphane (3.62 g,8.52 mmol), and 1,4-dioxane (453 mL). The catalyst-ligand mixture wasdegassed via vacuum/nitrogen purge (3 times) and heated at about 80° C.for about 10 min. Then 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (30.0g, 85 mmol), tert-butyl hydrazinecarboxylate (16.9 g, 128 mmol), andNaOt-Bu (12.28 g, 128 mmol) were added. After an additionalvacuum/nitrogen purge, the reaction was heated at about 80° C. Afterabout 50 min, the reaction mixture was cooled to ambient temperature andfiltered through a pad of silica gel (6 cm in height×6 cm in diameter),topped with Celite® (1 cm in height×6 cm in diameter), while washingwith EtOAc (3×150 mL). Water (300 mL) was added to the filtrate and theorganic layer was separated. The aqueous layer was extracted withadditional EtOAc (3×200 mL). The combined organic extracts were washedwith saturated aqueous NH₄Cl, saturated aqueous NaHCO₃, and brine (400mL each), dried over anhydrous MgSO₄, filtered, and concd under reducedpressure to give a dark brown oil (45 g). The brown oil was dissolved inDCM (250 mL), silica gel (200 g) was added, and the mixture was concdunder reduced pressure. The resulting silica mixture was purified usingsilica gel chromatography eluting with a gradient of 25-65% EtOAc inheptane to give a mixture of tert-butyl2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate [majorregioisomer] and tert-butyl1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate [minorregioisomer] (18.8 g, 50%): LC/MS (Table 1, Method c) R_(t)=1.47 min; MSm/z: 404 (M+H)⁺.

Step D: 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine

To a mixture of tert-butyl2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate andtert-butyl 1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate(49.2 g, 122 mmol) in 1,4-dioxane (290 mL) was added HCl (4 M in1,4-dioxane, 226 mL, 902 mmol). The reaction was heated at about 60° C.for about 2.5 h and then cooled to about 15-20° C. The solid wascollected by vacuum filtration, washed with EtOAc (3×50 mL), and thentriturated with Et₂O (60 mL), collected by vacuum filtration and driedto a constant weight under vacuum to yield 35.6 g of solid. The solidwas stirred with a mixture of saturated aqueous NaHCO₃ and EtOAc (1:1,400 mL). After about 1 h, the solid was collected by vacuum filtration,washed with ice cold water (3×30 mL) and EtOAc (3×30 mL), and dried in avacuum oven to a constant weight to afford2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine as a tan solid (21.2 g,57%): LC/MS (Table 1, Method a) R_(t)=1.88 min; MS m/z: 304 (M+H)⁺.

Step E: sodium4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-dienolate

A round bottom flask was charged with THF (1.5 L) followed by theportionwise addition of NaH (60% dispersion in mineral oil, 70.0 g, 1.75mol). Additional THF (500 mL) was added and the resulting mixture wascooled to about −10° C. and ethyl propionylacetate (250 mL, 1.80 mol)was added dropwise over about 1 h in order to keep the internaltemperature below about 10° C. The resulting mixture was stirred atambient temperature for about 0.5 h to give a clear yellow solution, andmethyl 4-chloroacetoacetate (100 mL, 0.88 mol) was added dropwise overabout 5 min. The resulting mixture was heated at about 50° C. for about19 h to give a reddish orange suspension. The reaction mixture wascooled to ambient temperature, concd under reduced pressure and theresulting liquid was transferred to a beaker and diluted with water (350mL). The mixture was stirred in an ice bath for about 2 h. The solid wascollected by vacuum filtration and the filter cake was rinsed with water(150 mL) and dried under vacuum for about 1 h. The solid was suspendedin Et₂O (1.5 L), filtered, washed with Et₂O (1.5 L), and dried undervacuum. The resulting solid was azeotroped with toluene (1 L) to give asolid that was re-suspended in Et₂O (1 L) and collected by vacuumfiltration. The filter cake was washed with Et₂O (500 mL) and driedunder vacuum to give sodium4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-dienolate(204.2 g, 89%) as beige solid: ¹H NMR (DMSO-d₆) δ 3.94 (q, J=7.1 Hz,2H), 3.46 (s, 3H), 3.04 (q, J=7.2 Hz, 2H), 2.66 (s, 2H), 1.13 (t, J=7.1Hz, 3H), 0.99 (t, J=7.3 Hz, 3H).

Step F: ethyl 2-ethyl-4-oxocyclopent-2-enecarboxylate

A 5 L round bottom flask was charged with sodium4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-dienolate(316 g, 1205 mmol), KCl (126 g, 1687 mmol, JT-Baker), AcOH (241 mL, 4218mmol, JT-Baker), toluene (1850 mL) and water (130 mL). The reaction washeated at reflux for about 6 h then cooled to ambient temperature andadded dropwise to NaHCO₃ (8% aqueous, 3.5 L). The resulting biphasicmixture was extracted with MTBE (2×1.5 L). The combined organic layerswere washed with brine (1 L), dried over anhydrous MgSO₄ and concd underreduced pressure to give 191 g of crude material that was purified byvacuum distillation (97-99° C., 0.600 mm Hg) to give ethyl2-ethyl-4-oxocyclopent-2-enecarboxylate (160 g, 69%): ¹H NMR (CDCl₃) δ6.04 (m, 1H), 4.26-4.15 (m, 2H), 3.76-3.69 (m, 1H), 2.75-2.57 (m, 2H),2.56-2.44 (m, 2H), 1.32-1.26 (m, 3H), 1.23-1.18 (m, 3H).

Step G: (1S,2R,4S)-ethyl 2-ethyl-4-hydroxycyclopentanecarboxylate

A mixture of copper (I) chloride (0.136 g, 1.37 mmol),(S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.854 g, 1.37mmol), and NaOt-Bu (0.132 g, 1.37 mmol) in toluene (50 mL) was stirredat ambient temperature for about 15 min then cooled to about 5° C. andpolymethylhydrosiloxane (12 mL, 55 mmol) was added. The reaction mixturewas stirred for about 40 min at about 5° C. then cooled to about −12° C.A solution of ethyl 2-ethyl-4-oxocyclopent-2-enecarboxylate (5.00 g,27.4 mmol) and t-BuOH (14 mL, 148 mmol) in toluene (50 mL) was added inone portion and the reaction mixture was stirred for about 16 h at about−12° C. The reaction mixture was quenched by the addition of MeOH (50mL). The solvents were removed under reduced pressure. The residue wasdissolved in MeOH (35 mL) and filtered through a pad of Celite®. Thefiltrate was concd under reduced pressure and the residue was trituratedwith EtOAc (100 mL) and filtered. The filtrate was concd under reducedpressure and the residue was purified using silica gel chromatography(280 g) eluting with a gradient of 0-10% EtOAc in heptane to give(1S,2R,4S)-ethyl 2-ethyl-4-hydroxycyclopentanecarboxylate (1.11 g, 22%):¹H NMR (CDCl₃) δ 4.30 (m, 1H), 4.24-4.08 (m, 2H), 2.88 (td, J=2.1, 7.1Hz, 1H), 2.40 (dt, J=7.8, 14.0 Hz, 1H), 2.08-1.91 (m, 3H), 1.52-1.31 (m,3H), 1.29 (t, J=7.1 Hz, 3H), 0.94 (t, J=7.4 Hz, 3H).

Step H: (1S,2R,4S)-2-ethyl-4-hydroxycyclopentanecarboxylic acid

NaOH (1 N aqueous, 12 mL, 12 mmol) was added to (1S,2R,4S)-ethyl2-ethyl-4-hydroxycyclopentanecarboxylate (1.11 g, 5.96 mmol). Thereaction mixture was stirred at ambient temperature for about 3 days andthen extracted with Et₂O (3×25 mL). The Et₂O extracts were discarded andthe aqueous portion was cooled to about 0° C. HCl (5 N aqueous) wasslowly added to bring the pH to about 2. The resulting aqueoussuspension was extracted with EtOAc (3×40 mL). The combined organiclayers were washed with brine (2×80 mL), dried over anhydrous MgSO₄,filtered, and concd under reduced pressure to give(1S,2R,4S)-2-ethyl-4-hydroxycyclopentanecarboxylic acid (0.943 g, 100%)as clear oil: ¹H NMR (CDCl₃) δ 4.36 (tdd, J=2.6, 4.9, 7.4, 1H), 2.95(td, J=2.4, 7.3, 1H), 2.41 (dt, J=7.7, 14.1, 1H), 2.16-1.94 (m, 3H),1.65-1.49 (m, 1H), 1.49-1.32 (m, 2H), 0.96 (q, J=7.4, 3H).

Step I: (1S,4S,5R)-5-ethyl-2-oxabicyclo[2.2.1]heptan-3-one

To (1S,2R,4S)-2-ethyl-4-hydroxycyclopentanecarboxylic acid (0.943 g,5.96 mmol) in DCM (60 mL) was added TEA (2.5 mL, 18 mmol) and BOP-Cl(1.821 g, 7.15 mmol). The reaction mixture was stirred at ambienttemperature for about 2 h then poured into Et₂O (350 mL). The solid wasremoved by filtration while washing with Et₂O (50 mL). The filtrate wasconed under reduced pressure to give a yellow oil which was dissolved inDCM (5 mL) and Et₂O was added to give a solid. The supernatant wasdecanted and the solid was washed with additional Et₂O. The combinedorganic extracts were coned under reduced pressure to give crude(1S,4S,5R)-5-ethyl-2-oxabicyclo[2.2.1]heptan-3-one containing about 15mol % TEA (0.912 g, 99%): ¹H NMR (CDCl₃) δ 4.85 (s, 1H), 2.88 (s, 1H),2.19 (m, 2H), 2.08 (m, 1H), 1.69 (m, 1H), 1.41 (m, 3H), 0.97 (t, J=5.4,3H).

Step J:(1S,2R,4S)-2-ethyl-4-hydroxy-N′-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)cyclopentanecarbohydrazide

To (1S,4S,5R)-5-ethyl-2-oxabicyclo[2.2.1]heptan-3-one (0.835 g, 5.96mmol) in 1,4-dioxane (12 mL) was added2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (step D, 1.810 g, 5.96mmol). The reaction mixture was heated at about 80° C. for about 16 hthen cooled to ambient temperature. 1,4-Dioxane (25 mL) andtrimethylaluminum (2 N in toluene, 9 mL, 18 mmol) were addedsequentially. The reaction mixture was stirred at ambient temperaturefor about 30 min then HCl (1 N aqueous, 50 mL) was added dropwise andthe reaction mixture was stirred for about 30 min. The layers wereseparated and the aqueous portion was extracted with EtOAc (2×100 mL).The combined organic extracts were washed with water (10 mL), saturatedaqueous NaHCO₃ (15 mL), brine (15 mL) and dried over anhydrous MgSO₄,filtered, and coned under reduced pressure. The residue was purifiedusing silica gel chromatography (40 g) eluting with 100% EtOAc to give(1S,2R,4S)-2-ethyl-4-hydroxy-N′-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)cyclopentanecarbohydrazide(1.887 g, 71%): LC/MS (Table 1, Method b) R_(t)=2.05 min; MS m/z: 444(M+H)⁺.

Step K:(1S,2R,4R)-4-(4-cyanophenoxy)-2-ethyl-N-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)cyclopentanecarbohydrazide

To(1S,2R,4S)-2-ethyl-4-hydroxy-N-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)cyclopentanecarbohydrazide(0.885 g, 1.99 mmol) in THF (15 mL) was added 4-hydroxybenzonitrile(0.357 g, 2.99 mmol), triphenylphosphine (0.998 g, 2.99 mmol, polymerbound, 3 mmol/g), and TEA (1.3 mL, 9 mmol). DEAD (0.47 mL, 2.99 mmol)was added dropwise. The reaction mixture was stirred for about 1 h thenadditional triphenylphosphine (0.50 g, 1.5 mmol, polymer bound, 3mmol/g) and DEAD (0.2 mL, 1.3 mmol) were added and the reaction mixturewas stirred at ambient temperature for about 16 h. The solid was removedby filtration while washing with DCM (5×5 mL) then MeOH (4×5 mL). Thefiltrate was concd under reduced pressure and the residue was purifiedusing silica gel chromatography (40 g) eluting with a gradient of 0-40%EtOAc in DCM to give(1S,2R,4R)-4-(4-cyanophenoxy)-2-ethyl-N′-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)cyclopentanecarbohydrazide(0.958 g, 88%) as a yellow foam: LC/MS (Table 1, Method b) R_(t)=2.56min; MS m/z: 545 (M+H)⁺.

Step L:4-((1R,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyloxy)benzonitrile

To(1S,2R,4R)-4-(4-cyanophenoxy)-2-ethyl-N-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)cyclopentanecarbohydrazide(0.958 g, 1.76 mmol) in 1,4-dioxane (18 mL) was added DIEA (1.2 mL, 7.0mmol) and thionyl chloride (0.4 mL, 5.3 mmol). The reaction mixture washeated at about 80° C. for about 2 h. The solvent was removed underreduced pressure and the residue was purified using silica gelchromatography (80 g) eluting with a gradient of 20-80% EtOAc in DCM togive4-((1R,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyloxy)benzonitrile(0.620 g, 67%): LC/MS (Table 1, Method b) R_(t)=2.65 min; MS m/z: 527(M+H)⁺.

Step M:4-((1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyloxy)benzonitrile

To4-(((1R,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclo-pentyloxy)benzonitrile(0.826 g, 1.57 mmol) in 1,4-dioxane (16 mL) was added Na₂CO₃ (2 Naqueous solution, 16 mL, 31 mmol). The reaction mixture was heated atabout 80° C. for about 16 h. The layers were separated and the aqueousportion was extracted with EtOAc (3×40 mL). The combined organic layerswere washed with saturated aqueous NaHCO₃ (2×30 mL), brine (30 mL),dried over anhydrous MgSO₄, filtered, and concd under reduced pressure.The residue was purified by using General Procedure AA (Table 2, Method17, R_(t)=19.2 min, or =negative) to give4-((1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyloxy)benzonitrile(0.298 g, 51%): LC/MS (Table 1, Method b) R_(t)=2.07 min; MS m/z: 373(M+H)⁺.

Example #5*N-(((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)(pyrrolidin-1-yl)methylene)cyanamide

Step A: 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine

To a solution of 3,5-dibromopyrazin-2-amine (125 g, 494 mmol), TEA(207.0 mL, 1483 mmol), and copper (I) iodide (0.941 g, 4.94 mmol) in THF(1255 mL) was added PdCl₂(PPh₃)₂ (3.47 g, 4.94 mmol). The reactionmixture was cooled at about −5-0° C. and a solution of(trimethylsilyl)acetylene (65.0 mL, 470 mmol) in THF (157 mL) was addeddropwise over about 15 min. The reaction mixture was stirred at about−5-0° C. for about 1.5 h and then allowed to warm to rt overnight. Thereaction mixture was then filtered through a Celite® pad and washed withTHF until no further product eluted. The filtrate was concd underreduced pressure to give a brown-orange solid. The solid was trituratedand sonicated with warm petroleum ether (b.p. 30-60° C., 400 mL), cooledto rt, collected, washed with petroleum ether (b.p. 30-60° C.; 2×60 mL),and dried to give 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine(124 g, 93%, 93% purity) as a brown solid: LC/MS (Table 1, Method b)R_(t)=2.51 min; MS m/z: 270, 272 (M+H)⁺.

Step B: 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine

To a solution of 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine(3.00 g, 11.1 mmol) in DMF (60 mL) at about 0° C. was added NaH (60%dispersion in mineral oil, 0.577 g, 14.4 mmol) in three portions. Afterabout 15 min, p-toluenesulfonyl chloride (2.75 g, 14.4 mmol) was addedand the reaction was allowed to warm slowly to ambient temperature.After about 16 h, the reaction mixture was poured onto ice-cold water(120 mL) and the precipitate was collected by vacuum filtration. Thecrude solid was dissolved in DCM (15 mL) and purified by silica gelchromatography eluting with DCM to give2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (2.16 g, 52%): LC/MS (Table 1,Method c) R_(t)=1.58 min; MS m/z: 352, 354 (M+H)⁺.

Step C: (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride

A 5 L reactor was charged with 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine(98.8 g, 281 mmol), zinc dust (3.50 g, 53.3 mmol), palladium(II)trifluoroacetate (4.0 g, 12 mmol), andracemic-2-(di-t-butylphosphino)-1,1′-binapthyl (9.8 g, 24.7 mmol). Theflask was equipped with a powder addition device into which zinc cyanide(10.0 g, 157 mmol) was placed to be added at a later step. The vesselwas purged with argon for no longer than about 30 min and then argonsparged DMA (2 L) was added to the reactor. The mixture was stirred andheated to about 50° C. while maintaining an argon atmosphere. Theresulting dark brown solution was further heated to about 95° C. whileadding the zinc cyanide, from the powder addition device, portionwiseover about 15 min. Upon reaching about 95° C., the brown mixture wasstirred for about an additional 16 h. The reaction mixture was cooled toambient temperature, resulting in the precipitation of salts. Themixture was filtered through a Buchner funnel containing filter-aid andthe filter cake was washed with DMA (20 mL). A solution of the crudeproduct in DMA was added to cold (<10° C.) water (16 L) and stirred forabout 30 min. The resulting suspension was filtered and the filter cakewas rinsed again with water (1 L). The resulting wet cake was dried in avacuum oven at about 50° C. The crude solid was dissolved in DCM (1.5 L)and further dried over anhydrous MgSO₄. After filtration, the solutionwas passed through a pad of silica (140 g), using DCM as the eluentuntil only predominantly impurities were detected eluting off the pad.The solvent was removed under reduced pressure and the crude solid wastriturated with MeOH/DCM (4:1, 10 volumes of solvent per gram of crudesolid) at ambient temperature for about 5 h. The solid was filtered andwashed with MeOH (300 mL). The product was dried in a vacuum oven toprovide 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbonitrile (58.8 g, 70%)as a white solid: ¹H NMR (CDCl₃) δ 8.67 (s, 1H), 8.21 (d, J=4.2 Hz, 1H),8.07 (d, J=8.4 Hz, 2H), 7.34 (d, J=8.1 Hz, 2H), 6.89 (d, J=4.2 Hz, 1H),2.42 (s, 3H). A 2-L 316-stainless steel pressure reactor was chargedwith 5 wt % Pd/C (15.4 g of 63.6 wt % water wet material, 5.6 g drybasis, 2.6 mmol Johnson Matthey A503032-5),5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbonitrile (55 g, 184 mmol), THF(1.1 L), deionized water (165 mL), HCl (37 wt % aqueous, 30 mL, 369mmol) and quinoline (1.1 mL, 9.0 mmol). The vessel was purged,pressurized, and maintained at 40 psi with hydrogen supplied from a highpressure reservoir. The mixture was vigorously agitated at about 25° C.After about 5 h the reactor was vented and purged with nitrogen toremove most of the dissolved hydrogen, and the reaction mixture wasfiltered to remove the catalyst. The reactor and catalyst cake wererinsed with THF:water (1:1, 2×40 mL). The combined filtrate and rinseswere concd and EtOH (500 mL) was added then removed under reducedpressure. After two further azeotropes using EtOH (2×500 mL), the cruderesidue was concd under reduced pressure to give a residue (76 g) thatwas suspended in EtOH (550 mL) and stirred at ambient temperature forabout 4 h. The solid was collected by filtration and washed with coldEtOH (50 mL). The wet cake was dried in a vacuum oven to provide(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride (51.2g, 82%) as a white solid: LC/MS (Table 1, Method a) R_(t)=1.44 min; MSm/z: 303 (M+H)⁺.

Step D: 4-methylpiperidine-3-carboxylic acid hydrochloride

AcOH (380 mL) was added to 4-methylnicotinic acid hydrochloride (50.5 g,291 mmol, Maybridge) and PtO₂ (5.05 g, 22.2 mmol, Johnson Matthey) in a600 mL stainless steel reactor. The mixture was stirred under 220 psi ofhydrogen at ambient temperature for about 14 hr. The supernatantsolution was filtered through a nylon membrane and rinsed with enoughAcOH until only the catalyst remained. The filtrate was concd underreduced pressure to give a clear oil that solidified upon cooling toambient temperature to give crude 4-methylpiperidine-3-carboxylic acidwith AcOH as an excipient (88.94 g, 170% crude): LC/MS (Table 1, Methodb) R_(t)=0.44 min; MS m/z: 144 (M+H)⁺.

Step E: (3R,4R)-ethyl 4-methylpiperidine-3-carboxylate(2S,3S)-2,3-dihydroxysuccinate

Crude racemic 4-methylpiperidine-3-carboxylic acid hydrochloride (−70%chemical purity, approximately 15:1 cis:trans) in AcOH (2:1, 300 g) wasdissolved in EtOH (1500 mL) and sparged with HCl (gas) for about 15 min.The reaction mixture was fitted with a balloon to allow for expansionthen heated to about 85° C. After about 48 h, the reaction mixture wascooled to ambient temperature and concd in vacuo to provide a thicksyrup containing racemic ethyl 4-methylpiperidine-3-carboxylic acidhydrochloride (260 g). To this ester was added CHCl₃ (1000 mL) followedby saturated aqueous NaHCO₃ (500 mL) and NH₄OH (15% aqueous, 500 mL).The organic layer was separated and the aqueous layer was furtherextracted with CHCl₃ (1000 mL). The combined organic layers were driedover anhydrous Na₂SO₄, filtered, and then concd in vacuo to providecrude ethyl 4-methylpiperidine-3-carboxylate (200 g) as an oil. To aslurry of (2S,3S)-2,3-dihydroxysuccinic acid (150 g, 1001 mmol) in MeOH(200 mL) was added a solution of crude ethyl4-methylpiperidine-3-carboxylate (200 g, 1168 mmol) in EtOAc (3000 mL).The mixture was stirred rapidly for about 3 h and the resulting solidswere collected by filtration to provide the(2S,3S)-2,3-dihydroxysuccinate salt as a white solid (245 g)(approximately 15:1 cis:trans, er=48:52 for cis stereoisomers). Thesolids were dissolved in MeOH (1000 mL) and EtOAc (3000 mL) was slowlyadded until solids began to form. After about 30 min, the solids werecollected by filtration and partially dried in vacuo to provide astereo-enriched mixture containing (3R,4R)-ethyl4-methylpiperidine-3-carboxylate (2S,3S)-2,3-dihydroxysuccinate as awhite solid (145 g) (approximately 15:1 cis:trans, er=60:40 for(3R,4R):(3S,4S) enantiomers). The above solids were dissolved in MeOH(1000 mL) and divided into four lots. Each lot (250 mL) was diluted withMeOH (500 mL) and EtOAc (3000 mL) was slowly added to the solution untilsolids formed. After about 4-15 h, the solids were collected byfiltration and dried in vacuo to provide multiple lots of partiallyresolved (3R,4R)-ethyl 4-methylpiperidine-3-carboxylate(2S,3S)-2,3-dihydroxysuccinate, these were combined and dissolved inMeOH (1000 mL) and EtOAc (4000 mL) was slowly added. After stirring forabout 1 h the solids were collected by filtration to provide(3R,4R)-ethyl 4-methylpiperidine-3-carboxy late (2S,3S)-2,3-dihydroxysuccinate (4.5 g) (approximately 15:1 cis:trans, er=98:2 for(3R,4R):(3S,4S) enantiomers), chiral analytical LC (Table 2, Method 30)minor isomer R_(t)=12.2 min; MS m/z: 343(M+(2S,3S)-2,3-dihydroxysuccinate+Na)⁺; major isomer R_(t)=10.6 min; MSm/z: 343 (M+(2S,3S)-2,3-dihydroxysuccinate+Na)⁺

Step F: (3R,4R)-1-(tert-butoxycarbonyl)-4-methylpiperidine-3-carboxylicacid

To a flask charged with (3R,4R)-ethyl 4-methylpiperidine-3-carboxylate(2S,3S)-2,3-dihydroxysuccinate (36.9 g, 115 mmol) was added a solutionof HCl (6 N aqueous, 191 mL). The reaction mixture was heated to about60° C. After about 2 h, the reaction mixture was heated to about 90° C.After about 4 h the reaction mixture was cooled to ambient temperatureand concd in vacuo. To the residue was added NaHCO₃ (122 g, 1148 mmol)and di-tert-butyl dicarbonate (37.6 g, 172 mmol) followed by a mixtureof 1,4-dioxane (500 mL) and water (500 mL). After about 2 h, Et₂O (500mL) and water (500 mL) were added to the reaction mixture. The pH wasadjusted to about 4 with 1 N aqueous HCl. The organic layer wasseparated, dried over anhydrous Na₂SO₄, filtered, and concd in vacuo toprovide a white solid. The solid was slurried in heptane and filtered toprovide (3R,4R)-1-(tert-butoxycarbonyl)-4-methylpiperidine-3-carboxylicacid (25 g, 89%) as a white solid: LC/MS (Table 1, Method b) R_(t)=1.90min; MS m/z: 244 (M+H)⁺.

Step G: (3R,4R)-tert-butyl4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)piperidine-1-carboxylate

To a slurry of (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanaminehydrochloride (34.0 g, 100 mmol, Example #5, Step C),(3R,4R)-1-(tert-butoxycarbonyl)-4-methylpiperidine-3-carboxylic acid(24.43 g, 100 mmol) and HATU (38.2 g, 100 mmol) in DCM (700 mL) wasadded DIEA (52.6 mL, 301 mmol). The reaction was stirred at ambienttemperature for about 45 min. The reaction was washed with saturatedaqueous NaHCO₃ (300 mL). The organic layer was separated, dried overanhydrous Na₂SO₄, filtered then concd in vacuo. The resulting residuewas purified by chromatography on silica gel (330 g) using 33-100% EtOAcin heptane to give(3R,4R)-tert-butyl-4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)piperidine-1-carboxylate(53 g, 100%) as a pale-yellow foam: LC/MS (Table 1, Method b) R_(t)=2.40min; MS m/z: 528 (M+H)⁺.

Step H: (3R,4R)-tert-butyl4-methyl-3-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate

A mixture of(3R,4R)-tert-butyl-4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl-carbamoyl)-piperidine-1-carboxylate(53 g, 100 mmol) and Lawesson's reagent (22.4 g, 55.2 mmol) in1,4-dioxane (500 mL) was heated at about 80° C. for about 1 h. Thereaction was allowed to cool to ambient temperature and then waspartitioned between EtOAc (1000 mL) and saturated aqueous NaHCO₃ (700mL). The organic layer was washed with additional saturated aqueousNaHCO₃ (700 mL), dried over anhydrous Na₂SO₄, filtered then concd invacuo. The resulting residue was dissolved in 1,4-dioxane (500 mL) thenmercury (II) trifluoroacetate (54.0 g, 127 mmol) was added. The reactionwas stirred at about 25° C. for about 1 h. The reaction was partitionedwith saturated aqueous Na₂S₂O₃ (500 mL)/water (500 mL) with DCM (1000mL). The layers were filtered through Celite® and the Celite® pad waswashed with DCM (500 mL). The combined layers were separated then theorganic layer was washed with saturated aqueous NaHCO₃ (800 mL). Theorganic layer was separated, dried over anhydrous Na₂SO₄, filtered, andthen coned in vacuo. The resulting residue was purified on silica gel(330 g) using 0-40% EtOAc in DCM to give (3R,4R)-tert-butyl4-methyl-3-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate(40.5 g, 79%) as a yellow foam: LC/MS (Table 1, Method b) R_(t)=2.62min; MS m/z: 510 (M+H)⁺.

Step I:(3R,4R)-tert-butyl-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidine-1-carboxylate

To a solution of (3R,4R)-tert-butyl4-methyl-3-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate(40 g, 78 mmol) in 1,4-dioxane (160 mL) was added NaOH (1 N aqueous, 157mL). The mixture was heated at about 60° C. for about 1 h. The mixturewas allowed to cool to ambient temperature. The mixture was partitionedwith HCl (4 N aqueous, 50 mL) and extracted with DCM (2×300 mL). Thecombined organic extracts were washed with brine (400 mL), dried overanhydrous Na₂SO₄, filtered then coned in vacuo. The product was purifiedon silica gel (330 g) using 1-5% MeOH in DCM to give (3R,4R)-tert-butyl3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidine-1-carboxylate(30 g, 99%): LC/MS (Table 1, Method b) R_(t)=2.00 min; MS m/z: 356(M+H)⁺.

Step J:1-((3R,4R)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazinehydrochloride

To a solution of (3R,4R)-tert-butyl3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methyl-piperidine-1-carboxylate(27.9 g, 78 mmol) in 1,4-dioxane (400 mL) was added HCl (4 N in1,4-dioxane, 58.9 mL, 235 mmol). The resulting suspension was heated atabout 60° C. for about 1 h. The reaction was allowed to cool to ambienttemperature and then was filtered, washed with 1,4-dioxane (100 mL)followed by Et₂O (100 mL), to give1-((3R,4R)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazinehydrochloride (20.6 g, 89%) as a tan solid: LC/MS (Table 1, Method b)R_(t)=1.27 min; MS m/z: 256 (M+H)⁺.

Step K:N-(((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)(pyrrolidin-1-yl)methylene)cyanamide

To a solution of diphenyl cyanocarbonimidate (0.163 g, 0.685 mmol) andDIEA (0.239 mL, 1.371 mmol) in MeCN (5 mL) was added1-((3R,4R)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazinehydrochloride (0.20 g, 0.68 mmol). The reaction was heated at about 80°C. for about 2 h. The reaction mixture was concd in vacuo. The residuewas dissolved in pyrrolidine (1.0 mL, 12 mmol) and transferred to asealed microwave vessel. The reaction was heated at about 120° C. forabout 30 min in a CEM microwave. The reaction mixture was concd in vacuoand purified by RP-HPLC (Table 1, Method i) to giveN-(((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)(pyrrolidin-1-yl)-methylene)cyanamide(0.030 g, 11%): LC/MS (Table 1, Method b) R_(t)=1.62 min; m/z: 377(M+H)⁺

Example #6*(R)-(3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-1-yl)(4,4-difluoropiperidin-1-yl)methanone

Step A: 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine

To a solution of 3,5-dibromopyrazin-2-amine (125 g, 494 mmol), TEA(207.0 mL, 1483 mmol), and copper (I) iodide (0.941 g, 4.94 mmol) in THF(1255 mL) was added PdCl₂(PPh₃)₂ (3.47 g, 4.94 mmol). The reactionmixture was cooled at about −5-0° C. and a solution of(trimethylsilyl)acetylene (65.0 mL, 470 mmol) in THF (157 mL) was addeddropwise over about 15 min. The reaction mixture was stirred at about−5-0° C. for about 1.5 h and then allowed to warm to rt overnight. Thereaction mixture was then filtered through a Celite® pad and washed withTHF until no further product eluted. The filtrate was concd underreduced pressure to give a brown-orange solid. The solid was trituratedand sonicated with warm petroleum ether (b.p. 30-60° C., 400 mL), cooledto rt, collected, washed with petroleum ether (b.p. 30-60° C.; 2×60 mL),and dried to give 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine(124 g, 93%, 93% purity) as a brown solid: LC/MS (Table 1, Method b)R_(t)=2.51 min; MS m/z: 270, 272 (M+H)⁺.

Step B: 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine

To a solution of 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine(3.00 g, 11.1 mmol) in DMF (60 mL) at about 0° C. was added NaH (60%dispersion in mineral oil, 0.577 g, 14.4 mmol) in three portions. Afterabout 15 min, p-toluenesulfonyl chloride (2.75 g, 14.4 mmol) was addedand the reaction was allowed to warm slowly to ambient temperature.After about 16 h, the reaction mixture was poured onto ice-cold water(120 mL) and the precipitate was collected by vacuum filtration. Thecrude solid was dissolved in DCM (15 mL) and purified by silica gelchromatography eluting with DCM to give2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (2.16 g, 52%): LC/MS (Table 1,Method c) R_(t)=1.58 min; MS m/z: 352, 354 (M+H)⁺.

Step C: (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride

A 5 L reactor was charged with 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine(98.8 g, 281 mmol), zinc dust (3.50 g, 53.3 mmol), palladium(II)trifluoroacetate (4.0 g, 12 mmol), andracemic-2-(di-t-butylphosphino)-1,1′-binapthyl (9.8 g, 24.7 mmol). Theflask was equipped with a powder addition device into which zinc cyanide(10.0 g, 157 mmol) was placed to be added later. The vessel was purgedwith argon for no longer than about 30 min and then argon sparged DMA (2L) was added to the reactor. The mixture was stirred and heated to about50° C. while maintaining an argon atmosphere. The resulting dark brownsolution was further heated to about 95° C. while adding the zinccyanide, from the powder addition device, portionwise over about 15 min.Upon reaching about 95° C., the brown mixture was stirred for about anadditional 16 h. The reaction mixture was cooled to ambient temperature,resulting in the precipitation of salts. The mixture was filteredthrough a Buchner funnel containing filter-aid and the filter cake waswashed with DMA (20 mL). A solution of the crude product in DMA wasadded to cold (<10° C.) water (16 L) and stirred for about 30 min. Theresulting suspension was filtered and the filter cake was rinsed againwith water 1 L). The resulting wet cake was dried in a vacuum oven atabout 50° C. The crude solid was dissolved in DCM (1.5 L) and furtherdried over anhydrous MgSO₄. After filtration, the solution was passedthrough a pad of silica (140 g), washing with additional solvent untilonly predominantly impurities were detected eluting off the pad. Thesolvent was removed under reduced pressure and the crude solid wastriturated with MeOH/DCM (4:1, 10 volumes of solvent per gram of crudesolid) at ambient temperature for about 5 h. The solid was filtered andwashed with MeOH (300 mL). The product was dried in a vacuum oven toprovide 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbonitrile (58.8 g, 70%)as a white solid: ¹H NMR (CDCl₃) δ8.67 (s, 1H), 8.21 (d, J=4.2 Hz, 1H),8.07 (d, J=8.4 Hz, 2H), 7.34 (d, J=8.1 Hz, 2H), 6.89 (d, J=4.2 Hz, 1H),2.42 (s, 3H). A 2-L 316-stainless steel pressure reactor was chargedwith 5 wt % Pd/C (15.4 g of 63.6 wt % water wet material, 5.6 g drybasis, 2.6 mmol, Johnson Matthey A503032-5),5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbonitrile (55 g, 184 mmol), THF(1.1 L), deionized water (165 mL), HCl (37 wt % aqueous, 30 mL, 369mmol) and quinoline (1.1 mL, 9.0 mmol). The vessel was purged,pressurized, and maintained at 40 psi with hydrogen supplied from a highpressure reservoir. The mixture was vigorously agitated at about 25° C.After about 5 h the reactor was vented and purged with nitrogen toremove most of the dissolved hydrogen, and the reaction mixture wasfiltered to remove the catalyst. The reactor and catalyst cake wererinsed with THF:water (1:1, 2×40 mL). The combined filtrate and rinseswere concd and EtOH (500 mL) was added. After two additional solventswitches with EtOH (2×500 mL), the crude residue was concd under reducedpressure to give a residue (76 g) that was suspended in EtOH (550 mL)and stirred at ambient temperature for about 4 h. The solid wascollected by filtration and washed with cold EtOH (50 mL). The wet cakewas dried in a vacuum oven to provide(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride (51.2g, 82%) as a white solid: LC/MS (Table 1, Method a) R_(t)=1.44 min; MSm/z: 303 (M+H)⁺.

Step D: (R)-tert-butyl3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)-piperidine-1-carboxylate

To a solution of (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanaminehydrochloride (5 g, 14.7 mmol) in DCM (78 mL) was added DIEA (7.7 mL,44.3 mmol) and stirred at ambient temperature for about 10 min followedby the addition of (R)—N-Boc-piperidine-3-carboxylic acid (3.38 g, 14.7mmol, CNH-Technologies) and HATU (5.61 g, 14.7 mmol). The mixture wasstirred for about 1 h at ambient temperature and to it was added water(30 mL) and the layers were separated. The organic layer was washed withsaturated aqueous NaHCO₃ (30 mL) and brine (30 mL), dried over anhydrousMgSO₄, filtered, and concd under reduced pressure. The crude materialwas purified by silica gel chromatography eluting with a gradient of0-5% MeOH in DCM to afford crude (R)-tert-butyl3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)piperidine-1-carboxylate(7.58 g, 94%): LC/MS (Table 1, Method b) R_(t)=2.30 min; MS m/z: 514(M+H)⁺.

Step E: (R)-tert-butyl3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamothioyl)-piperidine-1-carboxylate

To a solution of (R)-tert-butyl3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)-piperidine-1-carboxylate(7.58 g, 13.8 mmol) in 1,4-dioxane (130 mL) was added Lawesson's reagent(3.37 g, 8.32 mmol) and the reaction mixture was heated to about 60° C.for about 2 h then cooled to ambient temperature and concd under reducedpressure. The crude residue was dissolved with EtOAc (40 mL) and washedwith saturated aqueous NaHCO₃, (3×40 mL), brine (30 mL), dried overanhydrous MgSO₄, filtered, and concd under reduced pressure. The crudematerial was purified by silica gel chromatography eluting with agradient of 0-5% MeOH in DCM to afford (R)-tert-butyl3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamothioyl)piperidine-1-carboxylate(5.6 g, 74%, UV purity 97%): LC/MS (Table 1, Method b) R_(t)=2.60 min;MS m/z: 530 (M+H)⁺.

Step F: (R)-tert-butyl3-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate

To a solution of (R)-tert-butyl3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamothioyl)-piperidine-1-carboxylate(5.61 g, 10.3 mmol) in 1,4-dioxane (96 mL) was added mercury (II)trifluoroacetate (4.38 g, 10.3 mmol) and the reaction mixture wasstirred at ambient temperature for about 2 h then filtered through a padof Celite®. The Celite® pad was rinsed with EtOAc (50 mL) and thefiltrate was concd under reduced pressure. The crude residue wasdissolved in EtOAc (40 mL) and the organic phase was washed withsaturated aqueous NaHCO₃ (2×40 mL), brine (30 mL), dried over anhydrousMgSO₄, filtered, and concd under reduced pressure. The crude materialwas purified by silica gel chromatography eluting with a gradient of0-5% MeOH in DCM to afford (R)-tert-butyl3-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate(4.4 g, 87%): LC/MS (Table 1, Method b) R_(t)=2.49 min; MS m/z: 496(M+H)⁺.

Step G: (R)-tert-butyl3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate

To a solution of (R)-tert-butyl3-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate(4.44 g, 8.96 mmol) in 1,4-dioxane (54 mL) was added NaOH (2 N aqueous,8.9 mL, 18 mmol), and the resulting mixture was heated at about 60° C.for about 3 h. The reaction was cooled to ambient temperature and EtOAc(30 mL) and saturated aqueous NH₄Cl (20 mL) were added. The organiclayer was separated and the aqueous layer was further extracted withEtOAc (40 mL). The combined organic layers were washed with brine (40mL), dried over anhydrous MgSO₄, filtered, and concd under reducedpressure. The material was purified by silica gel chromatography elutingwith a gradient of 0-10% MeOH in DCM to afford (R)-tert-butyl3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate(2.80 g, 92%): LC/MS (Table 1, Method b) R_(t)=1.85 min; MS m/z: 342(M+H)⁺.

Step H: (R)-1-(piperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazinehydrochloride

A round bottom flask was charged with (R)-tert-butyl3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate(2.8 g, 8.20 mmol), 1,4-dioxane (24 mL) and HCl (4 N in 1,4-dioxane, 6.2mL, 24.6 mmol). The reaction mixture was heated at about 60° C. forabout 18 h. The reaction mixture was cooled to ambient temperature, Et₂O(40 mL) was added and the mixture was stirred for about 15 min. Thesolid was collected by vacuum filtration and washed with Et₂O (50 mL)then dried in a vacuum oven at about 60° C. to afford(R)-1-(piperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazinehydrochloride as an off-white solid (2.4 g, 94%): LC/MS (Table 1, Methodb) R_(t)=0.81 min; MS m/z 242 (M+H)⁺.

Step I:(R)-(3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-1-yl)(4,4-difluoropiperidin-1-yl)methanone

To a solution of(R)-1-(piperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazinehydrochloride (0.24 g, 0.76 mmol) in pyridine (7.2 mL) was added CDI(0.14 g, 0.87 mmol) and the reaction mixture was stirred at about 50° C.for about 2 h. Additional CDI (0.02 g, 0.14 mmol) was added and thereaction mixture was stirred for about 1 h. To the reaction mixture wasadded 4,4-difluoropiperidine hydrochloride (0.12 g, 0.76 mmol). Thereaction mixture was heated to about 55° C. for about 1 h, cooled toambient temperature, and stirred for about 2 d. The solvent was removedunder reduced pressure and the crude residue dissolved with DCM (5 mL)and washed with water (2 mL). The aqueous layer was back extracted withDCM (2 mL). The combined organic extracts were washed with brine (3 mL),dried over anhydrous MgSO₄, filtered, and concd under reduced pressure.The crude material was purified by silica gel chromatography elutingwith a gradient of 0-5% MeOH in DCM to afford(R)-(3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-1-yl)(4,4-difluoropiperidin-1-yl)methanone(0.146 g, 49%) as an off white solid: LC/MS (Table 1, Method b)R_(t)=1.70 min; MS m/z: 389 (M+H)⁺.

Example #7N-((1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentyl)-3,3,3-trifluoropropane-1-sulfonamide

Step A: 5-Bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine

To a solution of 3,5-dibromopyrazin-2-amine (125 g, 494 mmol), TEA(207.0 mL, 1483 mmol), and copper (I) iodide (0.941 g, 4.94 mmol) in THF(1255 mL) was added PdCl₂(PPh₃)₂ (3.47 g, 4.94 mmol). The reactionmixture was cooled at about −5-0° C. and a solution of(trimethylsilyl)acetylene (65.0 mL, 470 mmol) in THF (157 mL) was addeddropwise over about 15 min. The reaction mixture was stirred at about−5-0° C. for about 1.5 h and then allowed to warm to rt overnight. Thereaction mixture was then filtered through a Celite® pad and washed withTHF until no further product eluted. The filtrate was concd underreduced pressure to give a brown-orange solid. The solid was trituratedand sonicated with warm petroleum ether (b.p. 30-60° C., 400 mL), cooledto rt, collected, washed with petroleum ether (b.p. 30-60° C.; 2×60 mL),and dried to give 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine(124 g, 93%, 93% purity) as a brown solid: LC/MS (Table 1, Method b)R_(t)=2.51 min; MS m/z: 270, 272 (M+H)⁺.

Step B: 2-Bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine

To a solution of 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine(3.00 g, 11.1 mmol) in DMF (60 mL) at about 0° C. was added NaH (60%dispersion in mineral oil, 0.577 g, 14.4 mmol) in three portions. Afterabout 15 min, p-toluenesulfonyl chloride (2.75 g, 14.4 mmol) was addedand the reaction was allowed to warm slowly to ambient temperature.After about 16 h, the reaction mixture was poured onto ice-cold water(120 mL) and the precipitate was collected by vacuum filtration. Thecrude solid was dissolved in DCM (15 mL) and purified by silica gelchromatography eluting with DCM to give2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (2.16 g, 52%): LC/MS (Table 1,Method c) R_(t)=1.58 min; MS m/z: 352, 354 (M+H)⁺.

Step C: tert-Butyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate

2-Bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (30.0 g, 85 mmol), tert-butylcarbamate (14.9 g, 128 mmol), 325 mesh potassium carbonate (35.3 g, 256mmol), palladium acetate (0.19 g, 0.85 mmol) and9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (Xantphos) (0.99 g, 1.70mmol) were charged to a three-neck, 1 L cylindrical reactor equippedwith an over head stirrer, thermocouple and a reflux condenser. Thesolids were purged with argon for not less than 120 min.2-methyl-butanol (240 mL) and 1,4-dioxane (60 mL) were charged to aseparate 500 mL round bottom flask and purged with argon for not lessthan 60 min. The solvent mixture was transferred to the 1 L flask usinga cannula under a positive pressure of argon, the temperature was raisedto about 95° C. and the reaction mixture was stirred for about 3 h undera positive pressure of argon. The reaction mixture was cooled to about40° C., THF (100 mL) was added and filtered through a 2 inch pad ofcelite. The reaction mixture was split into 2 equal batches (about 200mL) and each of the batches were purified separately. Each batch wasdiluted with THF (250 mL) and was transferred to a 1 L cylindrical flaskequipped with a magnetic stir bar. A solution of L-cysteine (0.76 g),potassium bicarbonate (1.52 g) and sodium chloride (0.76 g) in water(250 mL) was added to the above flask and was allowed to stir for about2-4 h. The aqueous layer was separated. Formation of a rag layer wasobserved that was kept with the organic layer. The organic layer waswashed with saturated sodium chloride solution (100 mL) and the aqueouslayer was separated. Charcoal (0.76 g) was added to the flask, stirredfor about 2-4 h, filtered through a 2 inch pad of celite, rinsed withTHF (30 mL) and concentrated in vacuo at about 60° C. to obtain anoil/solid slurry. A mixture of isopropanol (50 mL) and heptanes (15 mL)were added to the oil/solid slurry and concentrated in vacuo to obtainlight yellow colored solid. Isopropanol (90 mL) was added to the solid,heated to about 60° C. and mixed for about 1 h. The mixture was allowedto cool to room temperature with stirring, solids were filtered off,rinsed with heptane (40 mL) and dried overnight in a vacuum oven atabout 50° C. The 2 batches were combined to obtain tert-butyl5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (12.87 g), as a lightyellow colored solid. ¹H NMR (400 MHz, DMSO) δ 10.11 (s, 1H), 8.77 (s,1H), 8.16 (d, J=4.1 Hz, 1H), 7.99-7.92 (m, 2H), 7.40 (d, J=8.4 Hz, 2H),6.83 (d, J=4.1 Hz, 1H), 2.32 (s, 3H), 1.46 (s, 9H).

Step D: 5-Tosyl-5H-pyrrolo[2,3-b]pyrazin-2-amine

tert-Butyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (14.0 g, 36.0mmol) and tetrahydrofuran (28 mL) were charged to a 500 mL round bottomflask containing a magnetic stir bar. Phosphoric acid (10 equiv, 85%,20.8 ml, 360 mmol) was added over about 5 minutes via needle andsyringe. Upon addition, effervescing occurred and solids formed. Theresultant slurry was heated to about 65° C. (bath temperature); uponreaching temperature all solids dissolved. After about 1 hr, there wasno starting material present. The hot reaction mixture was diluted withtetrahydrofuran (115 mL); then the solution was allowed to cool to roomtemperature. A solution of potassium phosphate tribasic (35.3 g, 360mmol) in water (145 mL) was prepared and added to the mixture over about20 minutes with vigorous stirring. The biphasic mixture was transferredto a separatory funnel using THF and water. The layers were separatedand the organic layer was transferred to a 500 mL round bottom flask.Water (100 mL) was added to the flask and the organics are removed underreduced pressure. This resulted in a suspension of solids in water,which was allowed to slurry for about 30 minutes. The solids wereisolated by vacuum filtration and placed in a vacuum oven to dry (oventemperature about 50° C.) for about 16 hours.5-Tosyl-5H-pyrrolo[2,3-b]pyrazin-2-amine was isolated as an off whitesolid (10.1 g, 97%). ¹H NMR (400 MHz, d₆-DMSO) δ 7.88-7.84 (m, 3H), 7.64(s, 1H), 7.39 (d, J=8.4, 2H), 6.55 (d, J=4.0, 1H), 6.31 (s, 2H), 2.33(s, 3H)

Step E: Sodium4-(ethoxycarbonyl)-2-(methoxycarbonyl)-3-methylcyclopenta-1,3-dienolate

In a 12 L round bottom flask, NaH (60% dispersion in mineral oil, 159 g,3985 mmol) was added in portions to stirred anhydrous THF (4004 mL) togive a gray suspension. The mixture was cooled to about 5° C. in anice/salt bath before ethyl acetoacetate (506 mL, 3985 mmol, Alfa Aesar)in anhydrous THF (200 mL) was added dropwise via an addition funnel overabout 1 h during which time the temperature gradually increased to about18° C. After the addition was complete, the reaction was stirred atambient temperature for about 1 h and then a solution of methyl4-chloroacetoacetate (230 mL, 1993 mmol, Oakwood) in anhydrous THF (200mL) was added dropwise via an addition funnel over about 1 h. Theresulting mixture was stirred at ambient temperature for about 2 h andthen heated at about 50° C. for about 16 h. The reaction mixture wasconcd in vacuo. The orange solid was cooled to about 5° C. and anice/water mixture (2 L) was added. The suspension was mixed by rotatingon the rotovap without vacuum for about 30 min. The solid was collectedby filtration and washed with ice-cold water (750 mL). Once most of thesolvent (about 90%) had been removed, the wet solid was triturated withMeCN (750 mL), stirred for about 30 min and then the solid was collectedby filtration while washing with Et₂O (2×500 mL). The solid was dried inair for about 16 h and then in vacuo at about 55° C. to give sodium4-(ethoxycarbonyl)-2-(methoxycarbonyl)-3-methylcyclopenta-1,3-dienolate(485 g, 98%): ¹H NMR (DMSO-d₆) δ 3.95 (q, J=7.1 Hz, 2H), 3.48 (s, 3H),2.69 (q, J=2.0 Hz, 2H), 2.47 (t, J=2.1 Hz, 3H), 1.15 (t, J=7.1 Hz, 3H).

Step F: Ethyl 2-methyl-4-oxocyclopent-2-enecarboxylate

In a 5 L round bottom flask, sodium4-(ethoxycarbonyl)-2-(methoxycarbonyl)-3-methylcyclopenta-1,3-dienolate(485 g, 1954 mmol), KCl (204 g, 2736 mmol, JT Baker), and AcOH (392 mL,6839 mmol, JT Baker) in toluene (1200 mL) and water (1200 mL) wereheated at reflux for about 6 h. The reaction mixture was allowed to coolto ambient temperature for about 16 h. The reaction mixture was thenpoured into a 12 L flask and diluted with water (3 L). Solid NaHCO₃ (450g, 5.3 mol) was added cautiously portionwise with stirring over about 1h. After an additional about 30 min of stirring, the basic aqueous phasewas separated and further extracted with Et₂O (4×400 mL). The combinedorganic layers were washed with water (4×500 mL) and saturated brine(500 mL), dried over anhydrous MgSO₄, filtered, and concd under reducedpressure to yield a yellow oil that was purified by vacuum distillation(about 92-94° C. at about 0.4 mmHg) to give ethyl2-methyl-4-oxocyclopent-2-enecarboxylate (229 g, 69%) as a yellow oil:¹H NMR (CDCl₃) δ 6.04-6.01 (m, 1H), 4.26-4.17 (m, 2H), 3.67 (m, 1H),2.72 (m, 1H), 2.62 (m, 1H), 2.16 (s, 3H), 1.32-1.27 (t, J=7.1 Hz, 3H).

Step G: Ethyl 2-methyl-4-oxocyclopentanecarboxylate

EtOAc (580 mL) was added to a round bottom flask charged with 10 wt %Pd/C (7.6 g, 7.1 mmol) at about 0° C., under a nitrogen atmosphere. Thecooling bath was removed and ethyl2-methyl-4-oxocyclopent-2-enecarboxylate (60.0 g, 357 mmol) was added.Hydrogen gas was bubbled through the mixture for about 5 min and themixture was then stirred under a hydrogen atmosphere (1 atmosphere) forabout 48 h. The hydrogen source was removed and the mixture was bubbledwith nitrogen for about 5 min and was filtered through a pad of Celite®.The filter cake was rinsed with EtOAc (500 mL). The filtrate was concdunder reduced pressure to give ethyl2-methyl-4-oxocyclopentanecarboxylate (59.9 g, 99%) as a yellow liquid:¹H NMR (CDCl₃) δ 4.23-4.14 (m, 2H), 3.18 (ddd, J=5.6, 6.8, 8.1 Hz, 1H),2.73-2.65 (m, 1H), 2.60 (ddd, J=1.7, 5.5, 18.7 Hz, 1H), 2.42-2.29 (m,2H), 2.15 (ddd, J=1.7, 7.9, 18.3 Hz, 1H), 1.29 (t, J=7.1 Hz, 3H), 1.07(d, J=7.0 Hz, 3H).

Step H: Ethyl 4-(dibenzylamino)-2-methylcyclopentanecarboxylate

A round bottom flask was charged with ethyl2-methyl-4-oxocyclopentanecarboxylate (10.0 g, 58.8 mmol) and DCE (180mL). The solution was cooled to about 0° C. and AcOH (5.7 mL, 100 mmol)and dibenzylamine (11.3 mL, 58.8 mmol) were added dropwise, resulting information of a thick suspension. The reaction mixture was warmed toabout 10° C. and sodium triacetoxyborohydride (21.2 g, 100 mmol) wasadded portionwise and the reaction mixture was stirred at ambienttemperature for about 20 h. The reaction mixture was slowly poured intostirred saturated aqueous NaHCO₃ (300 mL) and was stirred for about 20min. The layers were separated and the aqueous phase was extracted withDCM (3×100 mL). The combined organic extracts were washed with brine(2×100 mL), dried over anhydrous Na₂SO₄, and concd under reducedpressure. The crude yellow oil was purified via flash columnchromatography eluting with a gradient of 0-30% EtOAc in heptane to giveethyl 4-(dibenzylamino)-2-methylcyclopentanecarboxylate (15.5 g, 75%) asa colorless oil: ¹H NMR (pyridine-d₅) δ 7.53 (dd, J=0.9, 7.9 Hz, 4H),7.43-7.35 (m, 4H), 7.33-7.25 (m, 2H), 4.22-4.06 (m, 2H), 3.79 (d, J=14.2Hz, 2H), 3.70 (d, J=14.2 Hz, 2H), 3.34-3.22 (m, 1H), 2.76 (dd, J=7.9,16.6 Hz, 1H), 2.25-2.13 (m, 1H), 2.09-1.94 (m, 2H), 1.88-1.79 (m, 1H),1.52 (dd, J=10.5, 22.5 Hz, 1H), 1.16 (t, J=7.1 Hz, 3H), 0.98 (d, J=7.0Hz, 3H).

Step I: 4-(Dibenzylamino)-2-methylcyclopentanecarboxylic acid

Ethyl 4-(dibenzylamino)-2-methylcyclopentanecarboxylate (3.65 g, 10.38mmol) was dissolved in a mixture of HCl (6 N aqueous, 20 mL) and1,4-dioxane (50 mL) and the resulting mixture was heated at about 60° C.for about 72 h. The organic solvent was removed under reduced pressure.The aqueous phase was neutralized by the addition of saturated aqueousNaHCO₃ (40 mL) and extracted with EtOAc (50 mL). The organic phase waswashed with brine (40 mL), dried over anhydrous MgSO₄ and concd underreduced pressure to yield4-(dibenzylamino)-2-methylcyclopentanecarboxylic acid (3.3 g, 98%) as awhite amorphous solid: LC/MS (Table 1, Method a) R_(t)=1.66 min; MS m/z324 (M+H)⁺.

Step J:2-(2-Methyl-4-(dibenzylamino)cyclopentyl)-dimethylsulfoxonium-2-oxo-ethylide

Trimethylsulfoxonium chloride (26.1 g, 198 mmol), THF (202 ml), andpotassium tert-butoxide (23.35 g, 202 mmol) were added to a 500 mLjacketed flask under a nitrogen blanket. The suspension was stirred forabout 2 hours at about 65° C. before being cooled to about 0° C. In aseparate flask,(1S,2R,4S)-4-(dibenzylamino)-2-methylcyclopentanecarboxylic acid (21.4g, 66.2 mmol) was dissolved in THF (134 ml). HATU (31.4 g, 83 mmol) andtriethylamine (11.53 ml, 83 mmol) were added and the solution and mixedfor about 4 h. With the sulfur ylide suspension maintained between about0 and −5° C., the activated ester solution was filtered and then addeddropwise over about 3 h to the ylide suspension. The resultant brightyellow suspension was stirred for about 8 h at about 5° C. Water (340mL) and THF (30 mL) were added, and the mixture stirred for about 30 minat about 25° C. Aqueous sodium chloride (15% w/v, 60 mL) was added tothe solution and the layers separated. The aqueous layer was extractedwith EtOAc (60 mL). The combined organic layers were washed with aqueousNaCl (15% w/v, 3×100 mL). The solution was concentrated and the crudeoil was dissolved in methanol (150 mL) and water (150 mL) was added tothe slurry which is stirred for about 1 h at ambient temperature beforebeing cooled to about 10° C. and stirred overnight. The white solid wasfiltered and washed with chilled 1:1 MeOH/H2O (20 mL) and water (60 mL).The solid was dried in the vacuum oven to afford2-(2-methyl-4-(dibenzylamino)cyclopentyl)-dimethylsulfoxonium-2-oxo-ethylide(23.8 g, 90% yield). ¹H NMR (400 MHz, DMSO) δ 7.30 (ddd, J=15.0, 10.7,4.6 Hz, 8H), 7.21-7.14 (m, 2H), 4.67 (s, 1H), 3.71-3.52 (m, 4H), 3.39(d, J=3.9 Hz, 6H), 3.13-2.99 (m, 1H), 2.48-2.39 (m, 1H), 2.05-1.84 (m,2H), 1.82-1.66 (m, 2H), 1.43-1.30 (m, 1H), 0.90 (d, J=6.9 Hz, 3H).

Step K:1-((1S,2R,4S)-4-(dibenzylamino)-2-methylcyclopentyl)-2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)ethanone

To a 40 mL vial,2-(2-methyl-4-(dibenzylamino)cyclopentyl)-dimethylsulfoxonium-2-oxo-ethylide(4.02 g, 10.1 mmol), 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-amine (2.92 g,10.1 mmol), and chloro (1,5-cyclooctadiene) iridium(I) dimer (0.17 g,0.3 mmol, Alfa Aesar) was added. The reaction vessel was purged with N₂for about 10 min. To the reaction vessel, degassed CH₃Cl (13 mL) wasadded via syringe. The reaction mixture was purged with N₂ for about 10min and stirred under an atmosphere of N₂ at about 70° C. for about 68h. The reaction mixture was allowed to cool to ambient temperature. Thereaction mixture was purified by silica gel flash chromatography elutingwith a gradient of 0-25% EtOAc in heptane to yield1-((1S,2R,4S)-4-(dibenzylamino)-2-methylcyclopentyl)-2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)ethanone(8.61 g, 56%) as tan foam. ¹H NMR (400 MHz, DMSO) δ 7.91-7.80 (m, 4H),7.42-7.34 (m, 2H), 7.33-7.23 (m, 9H), 7.21-7.13 (m, 2H), 6.52 (d, J=3.5Hz, 1H), 4.23-4.04 (m, 2H), 3.63-3.48 (m, 4H), 3.19-3.09 (m, 1H),3.08-2.99 (m, 1H), 2.32 (s, 3H), 2.29-2.18 (m, 1H), 1.94-1.71 (m, 3H),1.37-1.23 (m, 1H), 0.86 (d, J=7.8 Hz, 3H).

Step L:(1S,3S,4R)—N,N-dibenzyl-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentanamine

To a 250 mL round-bottomed flask1-((1S,2R,4S)-4-(dibenzylamino)-2-methylcyclopentyl)-2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)ethanone(11.2 g, 17.51 mmol) in acetonitrile (60 ml) was added. The mixture wascooled with an ice bath and TFA (2.70 ml, 35.0 mmol) and TFAA (24.46 ml,175 mmol) was added. The resulting mixture was warmed and stirred atabout 40° C. for about 42 h. The reaction was then cooled in an ice bathand quenched with methanol (7 mL). After warming to ambient temperatureand stirring for about 1 h, it was poured into ethyl acetate (100 mL)and aqueous sodium carbonate (10% w/v, 200 mL). The layers wereseparated and the organic layer concentrated. The residue was dissolvedin THF (120 ml) and 2N sodium hydroxide (35.0 ml, 70.0 mmol) was added.The reaction mixture was warmed to about 60° C. and stirred for about 16h. After cooling to ambient temperature, 2-methyl-tetrahydrofuran (100mL) and brine (100 mL) were added and the layers separated. The aqueouslayer was extracted with 2-methyl-tetrahydrofuran (50 mL) and thecombined organic layers washed with brine (50 mL). The organic layer wasconcentrated, dissolved in EtOH (100 mL) and treated with charcoal (500mg) for about 1 h. The charcoal was filtered off and the ethanol removedunder reduced pressure. The residue was taken up in CHCl₃ (50 mL) warmedto about 50° C. and heptane (50 mL) was added. After cooling to ambienttemperature, the product was collected, washed with 1:2 CHCl₃:heptane(30 mL) and dried in a vacuum oven to afford(1S,3S,4R)—N,N-dibenzyl-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentanamineas a tan solid (5.1 g, 67%) ¹H NMR (400 MHz, DMSO) δ 12.18 (s, 1H), 8.52(s, 1H), 7.60 (s, 1H), 7.44-7.29 (m, 8H), 7.22 (t, J=7.2 Hz, 2H), 6.84(d, J=3.4 Hz, 1H), 3.86 (dd, J=17.6, 8.8 Hz, 1H), 3.77-3.59 (m, 4H),3.41-3.17 (m, 2H), 2.64-2.53 (m, 1H), 2.32-2.06 (m, 3H), 1.49-1.30 (m,1H), 0.40 (d, J=7.0 Hz, 3H).

Step M:(1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentanaminehydrochloride

To a 1.8 L stainless steel pressure bottle(1S,3S,4R)—N,N-dibenzyl-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentanamine(49 g, 112 mmol), 10% Pd(OH)₂/C (20 g, Johnson Matthey) and ethanol (750ml) was added under nitrogen. The reactor was purged with nitrogen thenhydrogen. The vessel was pressurized with hydrogen to about 30 psig. Themixture was agitated for about 22 hrs at about 50° C. After cooling toambient temperature, the reaction was filtered through a buchner funnelcontaining a glass fiber filter to remove the catalyst. Conc. HCl (12 M,16.7 mL) was added and concentrated under reduced pressure. The residuewas suspended in ethanol (100 mL) and EtOAc (100 mL), the solidscollected by filtration, washed with 1:1 EtOAc:EtOH (30 mL) and dried ina vacuum oven to afford(1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentanaminehydrochloride as an off-white solid (33.3 g, 86%). ¹H NMR (400 MHz,DMSO) δ 13.11 (s, 1H), 8.90 (s, 1H), 8.65-8.42 (m, 4H), 7.88 (t, J=3.1Hz, 1H), 7.21 (s, 1H), 4.20 (dd, J=17.3, 8.6 Hz, 1H), 3.75-3.52 (m, 1H),2.77-2.63 (m, 1H), 2.61-2.52 (m, 1H), 2.33 (ddd, J=31.4, 17.8, 8.8 Hz,2H), 1.54 (dt, J=12.7, 6.4 Hz, 1H), 0.50 (d, J=7.0 Hz, 3H).

Step N:N-((1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentyl)-3,3,3-trifluoropropane-1-sulfonamide

To a 2 L flask(1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentanaminehydrochloride (248.0 g, 733 mmol), water (1240 ml), THF (124 ml) andactivated carbon (24.12 g) was added and stirred for about 10 min. Theresulting mixture was filtered through celite rinsing with a mixture ofwater (100 mL) and THF (24 mL). Potassium carbonate (668 g, 4836 mmol)and THF (1736 ml) were added and a solution of3,3,3-trifluoropropane-1-sulfonyl chloride (315 g, 1524 mmol, Matrix) inTHF (620 ml) was added over about 1 hr. After cooling to ambienttemperature the layers were separated and the aqueous layer extractedwith THF (500 mL). The combined organic layers were washed with aqueousammonium chloride (3×100 mL) and concentrated to approximately 1 L.Water (1770 mL) was added slowly at about 50° C. and the slurry cooledto about 23° C. The solids were collected by filtration, washed with 35%THF in water (750 mL) and dried in a vacuum oven. The crude material wasdissolved in MeOH (4.5 L) and treated with activated carbon (28.3 g).After filtering through celite and rinsing with MeOH (500 mL), thesolution was concentrated under reduced pressure to approximately 1 Land water (800 mL) was added slowly at about 50° C. then cooled to 35°C. when additional water (360 mL) was added. The product was collectedby filtration, washed with 1:1 MeOH:water (2×350 mL) and dried in avacuum oven to affordN-((1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentyl)-3,3,3-trifluoropropane-1-sulfonamide(215.3 g, 71%) as a white crystalline solid (m.p. 225° C.). ¹H NMR (400MHz, DMSO) δ 11.99 (bs, 1H), 8.30 (s, 1H), 7.40 (bs, 1H), 7.38 (s, 1H),7.27-7.07 (m, 1H), 6.62 (d, J=3.4 Hz, 1H), 3.75 (dt, J=10.1, 7.8 Hz,1H), 3.70-3.55 (m, 1H), 3.15-3.02 (m, 2H), 2.61-2.40 (m, 2H), 2.40-2.29(m, 1H), 2.23 (dd, J=13.3, 6.9 Hz, 1H), 2.16-2.03 (m, 1H), 1.94-1.77 (m,1H), 1.20-0.99 (m, 1H), 0.17 (d, J=7.0 Hz, 3H).

Example #8*2-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)thiazole-5-carbonitrile

Step A: 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine

To a solution of 3,5-dibromopyrazin-2-amine (125 g, 494 mmol), TEA(207.0 mL, 1483 mmol), and copper (I) iodide (0.941 g, 4.94 mmol) in THF(1255 mL) was added PdCl₂(PPh₃)₂ (3.47 g, 4.94 mmol). The reactionmixture was cooled at about −5-0° C. and a solution of(trimethylsilyl)acetylene (65.0 mL, 470 mmol) in THF (157 mL) was addeddropwise over about 15 min. The reaction mixture was stirred at about−5-0° C. for about 1.5 h and then allowed to warm to rt overnight. Thereaction mixture was then filtered through a Celite® pad and washed withTHF until no further product eluted. The filtrate was concd underreduced pressure to give a brown-orange solid. The solid was trituratedand sonicated with warm petroleum ether (b.p. 30-60° C., 400 mL), cooledto rt, collected, washed with petroleum ether (b.p. 30-60° C.; 2×60 mL),and dried to give 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine(124 g, 93%, 93% purity) as a brown solid: LC/MS (Table 1, Method b)R_(t)=2.51 min; MS m/z: 270, 272 (M+H)⁺.

Step B: 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine

To a solution of 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine(3.00 g, 11.1 mmol) in DMF (60 mL) at about 0° C. was added NaH (60%dispersion in mineral oil, 0.577 g, 14.4 mmol) in three portions. Afterabout 15 min, p-toluenesulfonyl chloride (2.75 g, 14.4 mmol) was addedand the reaction was allowed to warm slowly to ambient temperature.After about 16 h, the reaction mixture was poured onto ice-cold water(120 mL) and the precipitate was collected by vacuum filtration. Thecrude solid was dissolved in DCM (15 mL) and purified by silica gelchromatography eluting with DCM to give2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (2.16 g, 52%): LC/MS (Table 1,Method c) R_(t)=1.58 min; MS m/z: 352, 354 (M+H)⁺.

Step C: tert-butyl2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate andtert-butyl 1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate

To a flask was added Pd₂(dba)₃ (3.90 g, 4.26 mmol),di-tert-butyl-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphane (3.62 g,8.52 mmol), and 1,4-dioxane (453 mL). The catalyst-ligand mixture wasdegassed via vacuum/nitrogen purge (3 times) and heated at about 80° C.for about 10 min. Then 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (30.0g, 85 mmol), tert-butyl hydrazinecarboxylate (16.9 g, 128 mmol), andNaOt-Bu (12.28 g, 128 mmol) were added. After an additionalvacuum/nitrogen purge, the reaction was heated at about 80° C. Afterabout 50 min, the reaction mixture was cooled to ambient temperature andfiltered through a pad of silica gel (6 cm in height×6 cm in diameter),topped with Celite® (1 cm in height×6 cm in diameter), while washingwith EtOAc (3×150 mL). Water (300 mL) was added to the filtrate and theorganic layer was separated. The aqueous layer was extracted withadditional EtOAc (3×200 mL). The combined organic extracts were washedwith saturated aqueous NH₄Cl, saturated aqueous NaHCO₃, and brine (400mL each), dried over anhydrous MgSO₄, filtered, and concd under reducedpressure to give a dark brown oil (45 g). The brown oil was dissolved inDCM (250 mL), silica gel (200 g) was added, and the mixture was concdunder reduced pressure. The resulting silica mixture was purified usingsilica gel chromatography eluting with a gradient of 25-65% EtOAc inheptane to give a mixture of tert-butyl2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate [majorregioisomer] and tert-butyl1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate [minorregioisomer] (18.8 g, 50%): LC/MS (Table 1, Method c) R_(t)=1.47 min; MSm/z: 404 (M+H)⁺.

Step D: 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine

To a mixture of tert-butyl2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate andtert-butyl 1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate(49.2 g, 122 mmol) in 1,4-dioxane (290 mL) was added HCl (4 M in1,4-dioxane, 226 mL, 902 mmol). The reaction was heated at about 60° C.for about 2.5 h and then cooled to about 15-20° C. The solid wascollected by vacuum filtration, washed with EtOAc (3×50 mL), and thentriturated with Et₂O (60 mL), collected by vacuum filtration and driedto a constant weight under vacuum to yield 35.6 g of solid. The solidwas stirred with a mixture of saturated aqueous NaHCO₃ and EtOAc (1:1,400 mL). After about 1 h, the solid was collected by vacuum filtration,washed with ice cold water (3×30 mL) and EtOAc (3×30 mL), and dried in avacuum oven to a constant weight to afford2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine as a tan solid (21.2 g,57%): LC/MS (Table 1, Method a) R_(t)=1.88 min; MS m/z: 304 (M+H)⁺.

Step E: sodium4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-dienolate

A round bottom flask was charged with THF (1.5 L) followed by theportionwise addition of NaH (60% dispersion in mineral oil, 70.0 g, 1.75mol). Additional THF (500 mL) was added and the resulting mixture wascooled to about −10° C. and ethyl propionylacetate (250 mL, 1.80 mol)was added dropwise over about 1 h in order to keep internal temperaturebelow about 10° C. The resulting mixture was stirred at ambienttemperature for about 0.5 h to give a clear yellow solution, and methyl4-chloroacetoacetate (100 mL, 0.88 mol) was added dropwise over about 5min. The resulting mixture was heated at about 50° C. for about 19 h togive a reddish orange suspension. The reaction mixture was cooled toambient temperature, concd under reduced pressure and the resultingliquid was transferred to a beaker and diluted with water (350 mL). Themixture was stirred in an ice bath for about 2 h. The solid wascollected by vacuum filtration and the filter cake was rinsed with water(150 mL) and dried under vacuum for about 1 h. The solid was suspendedin Et₂O (1.5 L), filtered, washed with Et₂O (1.5 L), and dried undervacuum. The resulting solid was azeotroped with toluene (1 L) to give asolid that was re-suspended in Et₂O (1 L) and collected by vacuumfiltration. The filter cake was washed with Et₂O (500 mL) and driedunder vacuum to give sodium4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-dienolate(204.2 g, 89%) as a beige solid: ¹H NMR (DMSO-d₆) δ 3.94 (q, J=7.1 Hz,2H), 3.46 (s, 3H), 3.04 (q, J=7.2 Hz, 2H), 2.66 (s, 2H), 1.13 (t, J=7.1Hz, 3H), 0.99 (t, J=7.3 Hz, 3H).

Step F: ethyl 2-ethyl-4-oxocyclopent-2-enecarboxylate

A 5 L round bottom flask was charged with sodium4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-dienolate(316 g, 1205 mmol), KCl (126 g, 1687 mmol, JT-Baker), AcOH (241 mL, 4218mmol, JT-Baker), toluene (1850 mL) and water (130 mL). The reaction washeated at reflux for about 6 h then cooled to ambient temperature andadded dropwise to NaHCO₃ (8% w/v aqueous, 3.5 L). The resulting biphasicmixture was extracted with MTBE (2×1.5 L). The combined organic layerswere washed with brine (1 L), dried over anhydrous MgSO₄ and concd underreduced pressure to give 191 g of crude material that was purified byvacuum distillation (97-99° C., 0.600 mm Hg) to give ethyl2-ethyl-4-oxocyclopent-2-enecarboxylate (160 g, 69%): ¹H NMR (CDCl₃) δ6.04 (m, 1H), 4.26-4.15 (m, 2H), 3.76-3.69 (m, 1H), 2.75-2.57 (m, 2H),2.56-2.44 (m, 2H), 1.32-1.26 (m, 3H), 1.23-1.18 (m, 3H).

Step G: ethyl 2-ethyl-4-oxocyclopentanecarboxylate

A round bottom flask was charged with 10 wt % Pd/C (10 g, 9.4 mmol). Theflask was cooled to about 0° C. and EtOAc (400 mL) was added under anitrogen atmosphere. The cooling bath was removed and ethyl2-ethyl-4-oxocyclopent-2-enecarboxylate (47.8 g, 263 mmol) was added.Hydrogen gas was bubbled through the mixture for about 5 min and themixture was then stirred under a hydrogen atmosphere for about 48 h. Thehydrogen source was removed and the mixture was bubbled with nitrogenfor about 5 min and was filtered through a pad of Celite®. The filtercake was rinsed with EtOAc (400 mL). The filtrate was coned underreduced pressure to give ethyl 2-ethyl-4-oxocyclopentanecarboxylate(about 9:1 mixture cis: trans) (48.0 g, 99%) as a yellow liquid: ¹H NMR(CDCl₃) δ 4.23-4.10 (m, 2H), 3.22 (m, 1H), 2.59-2.50 (m, 1H), 2.44-2.28(m, 3H), 2.26-2.16 (m, 1H), 1.58-1.46 (m, 1H), 1.41-1.30 (m, 1H),1.30-1.23 (m, 3H), 1.02-0.91 (m, 3H).

Step H: ethyl 4-(dibenzylamino)-2-ethylcyclopentanecarboxylate

A round bottom flask was charged with ethyl2-ethyl-4-oxocyclopentanecarboxylate (95.9 g, 521 mmol) and DCE (1.8 L).The solution was cooled to about 0° C. and AcOH (45 mL, 780 mmol) anddibenzylamine (120 mL, 625 mmol) were added dropwise, resulting in theformation of a thick suspension. The reaction mixture was warmed toabout 10° C. and additional DCE (500 mL) was added. Sodiumtriacetoxyborohydride (166 g, 781 mmol) was added portionwise and thereaction mixture was stirred at ambient temperature for about 20 h. Thereaction mixture was slowly poured into stirred saturated aqueous NaHCO₃(1.5 L), followed by the portionwise addition of solid NaHCO₃ (175 g).The mixture was stirred for about 2 h and the organic layer wasseparated, dried over anhydrous Na₂SO₄, and coned under reducedpressure. The crude yellow oil was purified by silica gel chromatographyeluting with 0-20% EtOAc in heptane to yield ethyl4-(dibenzylamino)-2-ethylcyclopentanecarboxylate (136.6 g, 72%) as awhite solid: LC/MS (Table 1, Method a) R_(t)=3.26 min; MS m/z: 366(M+H)⁺

Step I: ethyl 4-amino-2-ethylcyclopentanecarboxylate

To a vessel containing a slurry of 20 wt % Pd(OH)₂ on C (12.9 g, 18.4mmol) in EtOH (1.0 L) was added ethyl4-(dibenzylamino)-2-ethylcyclopentanecarboxylate (129 g, 352 mmol). Thereaction was shaken for about 90 min at about 50° C. under about 30 psiof hydrogen. After removal of the hydrogen source, a nitrogen atmospherewas introduced and the resulting mixture was filtered through a pad ofCelite® and the filtrate was coned under reduced pressure to give ethyl4-amino-2-ethylcyclopentanecarboxylate (64.5 g, 99%) as a yellow syrup:¹H NMR (CDCl₃) δ 4.03-3.88 (m, 2H), 3.17 (m, 1H), 2.68 (m, 1H),2.09-2.02 (m, 2H), 2.02-1.94 (m, 2H), 1.84 (m, 1H), 1.58-1.48 (m, 1H),1.32-1.18 (m, 1H), 1.09 (m, 3H), 1.03 (m, 2H), 0.78-0.69 (m, 3H).

Step J: (1S,2R,4S)-ethyl 4-acetamido-2-ethylcyclopentanecarboxylate

A solution of ethyl 4-amino-2-ethylcyclopentanecarboxylate (49.0 g, 264mmol) in pyridine (214 mL, 2645 mmol) was cooled to about 0° C. Aceticanhydride (125 mL, 1322 mmol) was added and stirring was continued atabout 0° C. for about 15 min. The resulting solution was warmed toambient temperature and stirred for about 12 h. The reaction was concdunder reduced pressure and EtOAc (500 mL) and HCl (1 N aqueous, 200 mL)were added. The layers were separated and the organic layer was washedwith HCl (1 N aqueous, 200 mL), saturated aqueous NaHCO₃ (2×200 mL) andbrine (150 mL), dried over anhydrous MgSO₄, filtered through a pad ofFlorisil® while washing with EtOAc (600 mL), and concd under reducedpressure to give an off-white solid (52 g) that was purified by usingGeneral Procedure AA (Table 2, Method 24, R_(t)=8.2 min, or=positive) togive (1S,2R,4S)-ethyl 4-acetamido-2-ethylcyclopentanecarboxylate (20.3g, 34%): LC/MS (Table 1, Method a) R_(t)=1.82 min; MS m/z: 228 (M+H)⁺.

Step K: (1S,2R,4S)-4-acetamido-2-ethylcyclopentanecarboxylic acid

To a flask containing (1S,2R,4S)-ethyl4-acetamido-2-ethylcyclopentanecarboxylate (9.44 g, 41.5 mmol) was addedNaOH (2 N aqueous, 141 mL, 282 mmol). After stirring at ambienttemperature for about 12 h, the reaction was acidified to about pH 1 bythe addition of 6 N aqueous HCl (50 mL) and extracted with EtOAc (3×500mL). The combined organic layers were washed with brine (100 mL), driedover anhydrous MgSO₄, filtered, and concd under reduced pressure to givecrude (1S,2R,4S)-4-acetamido-2-ethylcyclopentanecarboxylic acid (7.25 g,88%): LC/MS (Table 1, Method a) R_(t)=1.51 min; MS m/z: 200 (M−H)⁺.

Step L:N-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)acetamide

To a mixture of (1S,2R,4S)-4-acetamido-2-ethylcyclopentanecarboxylicacid (3.03 g, 15.2 mmol) in DCM (90 mL) was added2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (4.20 g, 13.8 mmol,Example #4, Step D), HATU (5.53 g, 14.5 mmol) and TEA (7.72 mL, 55.4mmol). After stirring at ambient temperature for about 2 h, the reactionwas diluted with water (60 mL). The layers were separated and theaqueous layer was extracted with DCM (3×50 mL). The combined organiclayers were washed with brine (50 mL), dried over anhydrous MgSO₄,filtered, and concd under reduced pressure. The crude material waspurified by silica gel chromatography eluting with a gradient of 0-5%MeOH in DCM to giveN-((1S,3R,4S)-3-ethyl-4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclopentyl)acetamide(7.0 g, 90%, 87% purity) as a tan foam: LC/MS (Table 1, Method a)R_(t)=1.96 min; MS m/z: 485 (M+H)⁺. To a solution of impureN-((1S,3R,4S)-3-ethyl-4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)-cyclo-pentyl)acetamide(9.40 g, 19.4 mmol) in 1,4-dioxane (100 mL) was added TEA (8 mL, 58mmol) and thionyl chloride (1.9 mL, 27.1 mmol). The reaction mixture washeated at about 80° C. for about 2 h, and then cooled to about 0° C. andsaturated aqueous NaHCO₃ and EtOAc (100 mL each) were added. The layerswere separated and the aqueous layer was extracted with additional EtOAc(2×100 mL). The combined organic layers were washed with brine (100 mL),dried over anhydrous MgSO₄, filtered, and concd under reduced pressure.The crude material was purified by silica gel chromatography elutingwith a gradient of 50-100% EtOAc/MeOH/Et₂NH (90:9:1) in EtOAc to giveN-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)acetamide(6.00 g, 66%): LC/MS (Table 1, Method a) R_(t)=2.03 min; MS m/z: 467(M+H)⁺.

Step M:(1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine

To a solution ofN-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)acetamide(6.0 g, 12.86 mmol, Example #8 Step L) in 1,4-dioxane (78 mL) was addedHCl (6 N aqueous, 75 mL, 450 mmol). The reaction mixture was heated atabout 95° C. for about 16 h. The reaction was cooled to ambienttemperature and the solvent was removed under reduced pressure. Theresidue was diluted with DCM (50 mL) and washed with saturated aqueousNaHCO₃ (100 mL). The aqueous portion was extracted with additional DCM(3×50 mL) and the combined organic layers were dried over anhydrousMgSO₄, filtered, and concd under reduced pressure. The crude materialwas purified by silica gel chromatography eluting with a gradient of0-100% DCM/MeOH/NH₄OH (950:45:5) in DCM to give(1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine(3.05 g, 56%) as a tan solid: LC/MS (Table 1, Method a) R_(t)=1.85 min;MS m/z: 425 (M+H)⁺.

Step N:2-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)thiazole-5-carbonitrile

A mixture of(1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine(0.20 g, 0.47 mmol), EtOH (1.3 mL), DIEA (0.33 mL, 1.88 mmol), and2-chlorothiazole-5-carbonitrile (0.082 g, 0.56 mmol, Ark Pharm) washeated in a CEM microwave at about 150° C. for about 30 min (250 psimaximum pressure, 5 min maximum ramp, 300 maximum watts). The reactionmixture was cooled to ambient temperature and concd under reducedpressure. The crude oil was dissolved in DCM (10 mL) and washed withwater (2×10 mL). The organic layer was dried over anhydrous MgSO₄,filtered, and concd under reduced pressure. The crude mixture waspurified by silica gel chromatography eluting with a gradient of 0-70%EtOAc in DCM to give2-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)thiazole-5-carbonitrile(0.21 g, 84%): LC/MS (Table 1, Method c) R_(t)=1.53 min; MS m/z: 533(M+H)⁺.

Step O:2-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)thiazole-5-carbonitrile

A mixture of2-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)thiazole-5-carbonitrile(0.21 g, 0.39 mmol), 1,4-dioxane (4.5 mL), EtOH (3.5 mL) and Na₂CO₃ (2 Naqueous, 5.8 mL, 15.7 mmol) was heated at about 50° C. for about 12 h.The reaction mixture was neutralized to pH 7 by the addition of AcOH(0.3 mL), washed with water (2×5 mL) and extracted with DCM (3×5 mL).The organic layer was dried over anhydrous MgSO₄, filtered, and concdunder reduced pressure. The crude material was purified by silica gelchromatography eluting with a gradient of 0-5% MeOH in DCM to give2-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)-thiazole-5-carbonitrile(0.09 g, 60%): LC/MS (Table 1, Method c) R_(t)=1.95 min; MS m/z: 379(M+H)⁺.

Example #9N-(4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)pyrrolidine-1-sulfonamide

Step A: 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine

To a solution of 3,5-dibromopyrazin-2-amine (125 g, 494 mmol), TEA(207.0 mL, 1483 mmol), and copper (I) iodide (0.941 g, 4.94 mmol) in THF(1255 mL) was added PdCl₂(PPh₃)₂ (3.47 g, 4.94 mmol). The reactionmixture was cooled at about −5-0° C. and a solution of(trimethylsilyl)acetylene (65.0 mL, 470 mmol) in THF (157 mL) was addeddropwise over about 15 min. The reaction mixture was stirred at about−5-0° C. for about 1.5 h and then allowed to warm to rt overnight. Thereaction mixture was then filtered through a Celite® pad and washed withTHF until no further product eluted. The filtrate was concd underreduced pressure to give a brown-orange solid. The solid was trituratedand sonicated with warm petroleum ether (b.p. 30-60° C., 400 mL), cooledto rt, collected, washed with petroleum ether (b.p. 30-60° C.; 2×60 mL),and dried to give 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine(124 g, 93%, 93% purity) as a brown solid: LC/MS (Table 1, Method b)R_(t)=2.51 min; MS m/z: 270, 272 (M+H)⁺.

Step B: 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine

To a solution of 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine(3.00 g, 11.1 mmol) in DMF (60 mL) at about 0° C. was added NaH (60%dispersion in mineral oil, 0.577 g, 14.4 mmol) in three portions. Afterabout 15 min, p-toluenesulfonyl chloride (2.75 g, 14.4 mmol) was addedand the reaction was allowed to warm slowly to ambient temperature.After about 16 h, the reaction mixture was poured onto ice-cold water(120 mL) and the precipitate was collected by vacuum filtration. Thecrude solid was dissolved in DCM (15 mL) and purified by silica gelchromatography eluting with DCM to give2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (2.16 g, 52%): LC/MS (Table 1,Method c) R_(t)=1.58 min; MS m/z: 352, 354 (M+H)⁺.

Step C: tert-butyl2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate andtert-butyl 1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate

To a flask was added Pd₂(dba)₃ (3.90 g, 4.26 mmol),di-tert-butyl-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphane (3.62 g,8.52 mmol), and 1,4-dioxane (453 mL). The catalyst-ligand mixture wasdegassed via vacuum/nitrogen purge (3 times) and heated at about 80° C.for about 10 min. Then 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (30.0g, 85 mmol), tert-butyl hydrazinecarboxylate (16.9 g, 128 mmol), andNaOt-Bu (12.28 g, 128 mmol) were added. After an additionalvacuum/nitrogen purge, the reaction was heated at about 80° C. Afterabout 50 min, the reaction mixture was cooled to ambient temperature andfiltered through a pad of silica gel (6 cm in height×6 cm in diameter),topped with Celite® (1 cm in height×6 cm in diameter), while washingwith EtOAc (3×150 mL). Water (300 mL) was added to the filtrate and theorganic layer was separated. The aqueous layer was extracted withadditional EtOAc (3×200 mL). The combined organic extracts were washedwith saturated aqueous NH₄Cl, saturated aqueous NaHCO₃, and brine (400mL each), dried over anhydrous MgSO₄, filtered, and concd under reducedpressure to give a dark brown oil (45 g). The brown oil was dissolved inDCM (250 mL), silica gel (200 g) was added, and the mixture was concdunder reduced pressure. The resulting silica mixture was purified usingsilica gel chromatography eluting with a gradient of 25-65% EtOAc inheptane to give a mixture of tert-butyl2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate [majorregioisomer] and tert-butyl1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate [minorregioisomer] (18.8 g, 50%): LC/MS (Table 1, Method c) R_(t)=1.47 min; MSm/z: 404 (M+H)⁺.

Step D: 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine

HCl (4 M in 1,4-dioxane, 226 mL, 902 mmol) was added to a mixture oftert-butyl 2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylateand tert-butyl1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate (49.2 g,122 mmol) in 1,4-dioxane (290 mL). The reaction was heated at about 60°C. for about 2.5 h and then cooled to about 15-20° C. The solid wascollected by vacuum filtration, washed with EtOAc (3×50 mL), and thentriturated with Et₂O (60 mL), collected by vacuum filtration and driedto a constant weight under vacuum to yield 35.6 g of crude solid. Thesolid was stirred with a mixture of saturated aqueous NaHCO₃ and EtOAc(1:1, 400 mL). After about 1 h, the solid was collected by vacuumfiltration, washed with ice cold water (3×30 mL) and EtOAc (3×30 mL),and dried in a vacuum oven to a constant weight to afford2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine as a tan solid (21.2 g,57%): LC/MS (Table 1, Method a) R_(t)=1.88 min; MS m/z: 304 (M+H)⁺.

Step E: tert-butyl4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)bicyclo[2.2.2]octan-1-ylcarbamate

A round bottom flask was charged with2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (3.75 g, 11.1 mmol),4-(tert-butoxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylic acid (3.0g, 11 mmol, Prime Organics), HATU (4.23 g, 11.1 mmol), TEA (6.2 mL, 44mmol), and DCM (65 mL). The reaction mixture was stirred at ambienttemperature for about 16 h. The reaction mixture was diluted with water(30 mL) and the initial layers that formed were separated. The remainingaqueous emulsion was filtered through Celite®. The filtrate layers wereseparated and the aqueous layer was extracted with additional DCM (60mL). The organic layer was washed with water (3×50 mL), dried overanhydrous MgSO₄, filtered, and concd under reduced pressure. The crudematerial was purified by silica gel chromatography eluting with agradient of 0-100% EtOAc in DCM to afford tert-butyl4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)bicyclo12.2.21 octan-1-ylcarbamate as a brown amorphous solid (5.38 g, 87%):LC/MS (Table 1, Method a) R_(t)=2.40 min; MS m/z 555 (M+H)⁺.

Step F:4-((6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-amine

To a solution of tert-butyl4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)-bicyclo[2.2.2]octan-1-ylcarbamate(6.1 g, 11.0 mmol), TEA (6.1 mL, 44.0 mmol) in 1,4-dioxane (110 mL) wasadded SOCl₂ (2.0 mL, 27.5 mmol). The reaction mixture was heated atabout 80° C. for about 2 h then cooled to ambient temperature. Thereaction mixture was washed with saturated aqueous NaHCO₃ (3×50 mL). Theaqueous portion was filtered to give4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]-octan-1-amineas a brown solid (1.17 g, 24%): LC/MS (Table 1, Method a) R_(t)=1.28min; MS m/z: 437 (M+H)⁺. The remaining filtrate was extracted with EtOAc(10 mL). The organic layer was dried over anhydrous MgSO₄, filtered, andconcd under reduced pressure to afford crude tert-butyl4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-ylcarbamate(3.5 g). The crude Boc-protected material was dissolved in 1,4-dioxane(38 mL) and HCl (4 N in 1,4-dioxane, 8 mL) was added. The reactionmixture was heated at about 50° C. for about 3 h. The precipitate formedwas filtered, dissolved in DCM (50 mL), and washed with saturatedaqueous NaHCO₃ (3×20 mL). The layers were separated and the organicportion was dried over anhydrous MgSO₄, filtered, and concd underreduced pressure to give additional4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-amineas a brown solid (2.3 g, 50% over 2 steps): LC/MS (Table 1, Method a)R_(t)=1.28 min; MS m/z: 437 (M+H)⁺.

Step G:N-(4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)pyrrolidine-1-sulfonamide

A round bottom flask was charged with4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-amine(0.12 g, 0.28 mmol), DIEA (0.48 mL, 2.8 mmol) in DMA (2.75 mL).Pyrrolidine-1-sulfonyl chloride (0.07 g, 0.41 mmol, Matrix) was addeddropwise and reaction mixture was stirred at ambient temperature forabout 1 h. K₂CO₃ (0.190 g, 1.37 mmol) was added and the reaction mixturewas stirred at ambient temperature for about 16 h. The solvent wasremoved under reduced pressure. The crude material was purified by flashchromatography on silica gel eluting with a gradient of 0-10% MeOH inDCM to giveN-(4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)pyrrolidine-1-sulfonamide,which was dissolved in NaOH (1 N aqueous, 1.10 mL, 1.10 mmol) and1,4-dioxane (1 mL) and heated at about 50° C. for about 1 h. The crudematerial was purified by preparative reverse phase HPLC (Table 2,Method 1) to giveN-(4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)pyrrolidine-1-sulfonamide(0.042 g, 37%) as a white solid: LC/MS (Table 1, Method a) R_(t)=1.81min; MS m/z 416 (M+H)⁺.

Example #10* (3R,4R)-phenyl3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidine-1-carboxylate

Step A: 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine

To a solution of 3,5-dibromopyrazin-2-amine (125 g, 494 mmol), TEA(207.0 mL, 1483 mmol), and copper (I) iodide (0.941 g, 4.94 mmol) in THF(1255 mL) was added PdCl₂(PPh₃)₂ (3.47 g, 4.94 mmol). The reactionmixture was cooled at about −5-0° C. and a solution of(trimethylsilyl)acetylene (65.0 mL, 470 mmol) in THF (157 mL) was addeddropwise over about 15 min. The reaction mixture was stirred at about−5-0° C. for about 1.5 h and then allowed to warm to rt overnight. Thereaction mixture was then filtered through a Celite® pad and washed withTHF until no further product eluted. The filtrate was concd underreduced pressure to give a brown-orange solid. The solid was trituratedand sonicated with warm petroleum ether (b.p. 30-60° C., 400 mL), cooledto rt, collected, washed with petroleum ether (b.p. 30-60° C.; 2×60 mL),and dried to give 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine(124 g, 93%, 93% purity) as a brown solid: LC/MS (Table 1, Method b)R_(t)=2.51 min; MS m/z: 270, 272 (M+H)⁺.

Step B: 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine

To a solution of 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine(3.00 g, 11.1 mmol) in DMF (60 mL) at about 0° C. was added NaH (60%dispersion in mineral oil, 0.577 g, 14.4 mmol) in three portions. Afterabout 15 min, p-toluenesulfonyl chloride (2.75 g, 14.4 mmol) was addedand the reaction was allowed to warm slowly to ambient temperature.After about 16 h, the reaction mixture was poured onto ice-cold water(120 mL) and the precipitate was collected by vacuum filtration. Thecrude solid was dissolved in DCM (15 mL) and purified by silica gelchromatography eluting with DCM to give2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (2.16 g, 52%): LC/MS (Table 1,Method c) R_(t)=1.58 min; MS m/z: 352, 354 (M+H)⁺.

Step C: (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride

A 5 L reactor was charged with 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine(98.8 g, 281 mmol), zinc dust (3.50 g, 53.3 mmol), palladium(II)trifluoroacetate (4.0 g, 12 mmol), andracemic-2-(di-t-butylphosphino)-1,1′-binapthyl (9.8 g, 24.7 mmol). Theflask was equipped with a powder addition device into which zinc cyanide(10.0 g, 157 mmol) was placed to be added at a later step. The vesselwas purged with argon for no longer than about 30 min and then argonsparged DMA (2 L) was added to the reactor. The mixture was stirred andheated to about 50° C. while maintaining an argon atmosphere. Theresulting dark brown solution was further heated to about 95° C. whileadding the zinc cyanide, from the powder addition device, portionwiseover about 15 min. Upon reaching about 95° C., the brown mixture wasstirred for about an additional 16 h. The reaction mixture was cooled toambient temperature, resulting in the precipitation of salts. Themixture was filtered through a Buchner funnel containing filter-aid andthe filter cake was washed with DMA (20 mL). A solution of the crudeproduct in DMA was added to cold (<10° C.) water (16 L) and stirred forabout 30 min. The resulting suspension was filtered and the filter cakewas rinsed again with water (1 L). The resulting wet cake was dried in avacuum oven at about 50° C. The crude solid was dissolved in DCM (1.5 L)and further dried over anhydrous MgSO₄. After filtration, the solutionwas passed through a pad of silica (140 g), using DCM as the eluentuntil only predominantly impurities were detected eluting off the pad.The solvent was removed under reduced pressure and the crude solid wastriturated with MeOH/DCM (4:1, 10 volumes of solvent per gram of crudesolid) at ambient temperature for about 5 h. The solid was filtered andwashed with MeOH (300 mL). The product was dried in a vacuum oven toprovide 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbonitrile (58.8 g, 70%)as a white solid: ¹H NMR (CDCl₃) δ 8.67 (s, 1H), 8.21 (d, J=4.2 Hz, 1H),8.07 (d, J=8.4 Hz, 2H), 7.34 (d, J=8.1 Hz, 2H), 6.89 (d, J=4.2 Hz, 1H),2.42 (s, 3H). A 2-L 316-stainless steel pressure reactor was chargedwith 5 wt % Pd/C (15.4 g of 63.6 wt % water wet material, 5.6 g drybasis, 2.6 mmol Johnson Matthey A503032-5),5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbonitrile (55 g, 184 mmol), THF(1.1 L), deionized water (165 mL), HCl (37 wt % aqueous, 30 mL, 369mmol) and quinoline (1.1 mL, 9.0 mmol). The vessel was purged,pressurized, and maintained at 40 psi with hydrogen supplied from a highpressure reservoir. The mixture was vigorously agitated at about 25° C.After about 5 h the reactor was vented and purged with nitrogen toremove most of the dissolved hydrogen, and the reaction mixture wasfiltered to remove the catalyst. The reactor and catalyst cake wererinsed with THF:water (1:1, 2×40 mL). The combined filtrate and rinseswere concd and EtOH (500 mL) was added then removed under reducedpressure. After two further azeotropes using EtOH (2×500 mL), the cruderesidue was concd under reduced pressure to give a residue (76 g) thatwas suspended in EtOH (550 mL) and stirred at ambient temperature forabout 4 h. The solid was collected by filtration and washed with coldEtOH (50 mL). The wet cake was dried in a vacuum oven to provide(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride (51.2g, 82%) as a white solid: LC/MS (Table 1, Method a) R_(t)=1.44 min; MSm/z: 303 (M+H)⁺.

Step D: 4-methylpiperidine-3-carboxylic acid hydrochloride

AcOH (380 mL) was added to 4-methylnicotinic acid hydrochloride (50.5 g,291 mmol, Maybridge) and PtO₂ (5.05 g, 22.2 mmol, Johnson Matthey) in a600 mL stainless steel reactor. The mixture was stirred under 220 psi ofhydrogen at ambient temperature for about 14 hr. The supernatantsolution was filtered through a nylon membrane and rinsed with enoughAcOH until only the catalyst remained. The filtrate was concd underreduced pressure to give a clear oil that solidified upon cooling toambient temperature to give crude 4-methylpiperidine-3-carboxylic acidwith AcOH as an excipient (88.94 g, 170%): LC/MS (Table 1, Method b)R_(t)=0.44 min; MS m/z: 144 (M+H)⁺.

Step E: (3R,4R)-ethyl 4-methylpiperidine-3-carboxylate(2S,3S)-2,3-dihydroxysuccinate

Crude racemic 4-methylpiperidine-3-carboxylic acid hydrochloride (−70%chemical purity, approximately 15:1 cis:trans) in AcOH (2:1, 300 g) wasdissolved in EtOH (1500 mL) and sparged with HCl (gas) for about 15 min.The reaction mixture was fitted with a balloon to allow for expansionthen heated to about 85° C. After about 48 h, the reaction mixture wascooled to ambient temperature and concd in vacuo to provide a thicksyrup containing racemic ethyl 4-methylpiperidine-3-carboxylic acidhydrochloride (260 g). To this ester was added CHCl₃ (1000 mL) followedby saturated aqueous NaHCO₃ (500 mL) and NH₄OH (15% aqueous, 500 mL).The organic layer was separated and the aqueous layer was furtherextracted with CHCl₃ (1000 mL). The combined organic layers were driedover anhydrous Na₂SO₄, filtered, and then concd in vacuo to providecrude ethyl 4-methylpiperidine-3-carboxylate (200 g) as an oil. To aslurry of (2S,3S)-2,3-dihydroxysuccinic acid (150 g, 1001 mmol) in MeOH(200 mL) was added a solution of crude ethyl4-methylpiperidine-3-carboxylate (200 g, 1168 mmol) in EtOAc (3000 mL).The mixture was stirred rapidly for about 3 h and the resulting solidswere collected by filtration to provide the(2S,3S)-2,3-dihydroxysuccinate salt as a white solid (245 g)(approximately 15:1 cis:trans, er=48:52 for cis stereoisomers). Thesolids were dissolved in MeOH (1000 mL) and EtOAc (3000 mL) was slowlyadded until solids began to form. After about 30 min, the solids werecollected by filtration and partially dried in vacuo to provide astereo-enriched mixture containing (3R,4R)-ethyl4-methylpiperidine-3-carboxylate (2S,3S)-2,3-dihydroxysuccinate as awhite solid (145 g) (approximately 15:1 cis:trans, er=60:40 for(3R,4R):(3S,4S) enantiomers). The above solids were dissolved in MeOH(1000 mL) and divided into four lots. Each lot (250 mL) was diluted withMeOH (500 mL) and EtOAc (3000 mL) was slowly added to the solution untilsolids formed. After about 4-15 h, the solids were collected byfiltration and dried in vacuo to provide multiple lots of partiallyresolved (3R,4R)-ethyl 4-methylpiperidine-3-carboxylate(2S,3S)-2,3-dihydroxysuccinate, these were combined and dissolved inMeOH (1000 mL) and EtOAc (4000 mL) was slowly added. After stirring forabout 1 h the solids were collected by filtration to provide(3R,4R)-ethyl 4-methylpiperidine-3-carboxylate(2S,3S)-2,3-dihydroxysuccinate (4.5 g) (approximately 15:1 cis:trans,er=98:2 for (3R,4R):(3S,4S) enantiomers), chiral analytical LC (Table 2,Method 30) minor isomer R_(t)=12.2 min; MS m/z: 343(M+(2S,3S)-2,3-dihydroxysuccinate+Na)⁺; major isomer R_(t)=10.6 min; MSm/z: 343 (M+(2S,3S)-2,3-dihydroxysuccinate+Na)+

Step F: (3R,4R)-1-(tert-butoxycarbonyl)-4-methylpiperidine-3-carboxylicacid

To a flask charged with (3R,4R)-ethyl 4-methylpiperidine-3-carboxylate(2S,3S)-2,3-dihydroxysuccinate (36.9 g, 115 mmol) was added a solutionof HCl (6 N aqueous, 191 mL). The reaction mixture was heated to about60° C. After about 2 h, the reaction mixture was heated to about 90° C.After about 4 h the reaction mixture was cooled to ambient temperatureand concd in vacuo. To the residue was added NaHCO₃ (122 g, 1148 mmol)and di-tert-butyl dicarbonate (37.6 g, 172 mmol) followed by a mixtureof 1,4-dioxane (500 mL) and water (500 mL). After about 2 h, Et₂O (500mL) and water (500 mL) were added to the reaction mixture. The pH wasadjusted to about 4 with 1 N aqueous HCl. The organic layer wasseparated, dried over anhydrous Na₂SO₄, filtered, and concd in vacuo toprovide a white solid. The solid was slurried in heptane and filtered toprovide (3R,4R)-1-(tert-butoxycarbonyl)-4-methylpiperidine-3-carboxylicacid (25 g, 89%) as a white solid: LC/MS (Table 1, Method b) R_(t)=1.90min; MS m/z: 244 (M+H)⁺.

Step G: (3R,4R)-tert-butyl4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)piperidine-1-carboxylate

To a slurry of (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanaminehydrochloride (34.0 g, 100 mmol, Example #5, Step C),(3R,4R)-1-(tert-butoxycarbonyl)-4-methylpiperidine-3-carboxylic acid(24.43 g, 100 mmol) and HATU (38.2 g, 100 mmol) in DCM (700 mL) wasadded DIEA (52.6 mL, 301 mmol). The reaction was stirred at ambienttemperature for about 45 min. The reaction was washed with saturatedaqueous NaHCO₃ (300 mL). The organic layer was separated, dried overanhydrous Na₂SO₄, filtered then concd in vacuo. The resulting residuewas purified by chromatography on silica gel (330 g) using 33-100% EtOAcin heptane to give(3R,4R)-tert-butyl-4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)piperidine-1-carboxylate(53 g, 96%) as a pale-yellow foam: LC/MS (Table 1, Method b) R_(t)=2.40min; MS m/z: 528 (M+H)⁺.

Step H: (3R,4R)-tert-butyl4-methyl-3-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate

A mixture of(3R,4R)-tert-butyl-4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl-carbamoyl)-piperidine-1-carboxylate(53 g, 100 mmol) and Lawesson's reagent (22.4 g, 55.2 mmol) in1,4-dioxane (500 mL) was heated at about 80° C. for about 1 h. Thereaction was allowed to cool to ambient temperature and then waspartitioned between EtOAc (1000 mL) and saturated aqueous NaHCO₃ (700mL). The organic layer was washed with additional saturated aqueousNaHCO₃ (700 mL), dried over anhydrous Na₂SO₄, filtered then concd invacuo. The resulting residue was dissolved in 1,4-dioxane (500 mL) thenmercury (II) trifluoroacetate (54.0 g, 127 mmol) was added. The reactionwas stirred at about 25° C. for about 1 h. The reaction was partitionedwith saturated aqueous Na₂S₂O₃ (500 mL)/water (500 mL) with DCM (1000mL). The layers were filtered through Celite® and the Celite® pad waswashed with DCM (500 mL). The combined layers were separated then theorganic layer was washed with saturated aqueous NaHCO₃ (800 mL). Theorganic layer was separated, dried over anhydrous Na₂SO₄, filtered, andthen concd in vacuo. The resulting residue was purified on silica gel(330 g) using 0-40% EtOAc in DCM to give (3R,4R)-tert-butyl4-methyl-3-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate(40.5 g, 79%) as a yellow foam: LC/MS (Table 1, Method b) R_(t)=2.62min; MS m/z: 510 (M+H)⁺.

Step I:(3R,4R)-tert-butyl-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidine-1-carboxylate

To a solution of (3R,4R)-tert-butyl4-methyl-3-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate(40 g, 78 mmol) in 1,4-dioxane (160 mL) was added NaOH (1 N aqueous, 157mL). The mixture was heated at about 60° C. for about 1 h. The mixturewas allowed to cool to ambient temperature. The mixture was partitionedwith HCl (4 N aqueous, 50 mL) and extracted with DCM (2×300 mL). Thecombined organic extracts were washed with brine (400 mL), dried overanhydrous Na₂SO₄, filtered then concd in vacuo. The product was purifiedon silica gel (330 g) using 1-5% MeOH in DCM to give (3R,4R)-tert-butyl3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidine-1-carboxylate(30 g, 99%): LC/MS (Table 1, Method b) R_(t)=2.00 min; MS m/z: 356(M+H)⁺.

Step J:1-((3R,4R)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazinehydrochloride

To a solution of (3R,4R)-tert-butyl3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methyl-piperidine-1-carboxylate(27.9 g, 78 mmol) in 1,4-dioxane (400 mL) was added HCl (4 N in1,4-dioxane, 58.9 mL, 235 mmol). The resulting suspension was heated atabout 60° C. for about 1 h. The reaction was allowed to cool to ambienttemperature and then was filtered, washed with 1,4-dioxane (100 mL)followed by Et₂O (100 mL), to give1-((3R,4R)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazinehydrochloride (20.6 g, 89%) as a tan solid: LC/MS (Table 1, Method b)R_(t)=1.27 min; MS m/z: 256 (M+H)⁺.

Step K: (3R,4R)-phenyl3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidine-1-carboxylate

To a solution of1-((3R,4R)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazinehydrochloride (0.06 g, 0.21 mmol) in MeCN (1 mL) at about 0° C. wasadded TEA (0.06 mL, 0.41 mmol), THF (0.6 mL) and DMAP (0.006 g, 0.050mmol) then phenyl chloroformate (0.026 mL, 0.206 mmol) and stirred forabout 1 h. The reaction mixture was warmed to ambient temperature andconcd under reduced pressure. The crude residue was dissolved in DCM (3mL) and washed with water (2 mL), dried over anhydrous MgSO₄, filtered,and concd under reduced pressure. The crude residue was dissolved in DCM(5 mL) and washed with water (2 mL) and brine (2 mL), dried overanhydrous MgSO₄, filtered, and concd under reduced pressure. Thematerial was purified by RP-HPLC (Table 1, Method g) to give(3R,4R)-phenyl3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidine-1-carboxylate(0.010 g, 11%): LC/MS (Table 1, Method b) R_(t)=1.95 min; MS m/z 376(M+H)⁺.

Example #11* (R)-cyclopentyl3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate

Step A: 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine

To a solution of 3,5-dibromopyrazin-2-amine (125 g, 494 mmol), TEA(207.0 mL, 1483 mmol), and copper (I) iodide (0.941 g, 4.94 mmol) in THF(1255 mL) was added PdCl₂(PPh₃)₂ (3.47 g, 4.94 mmol). The reactionmixture was cooled at about −5-0° C. and a solution of(trimethylsilyl)acetylene (65.0 mL, 470 mmol) in THF (157 mL) was addeddropwise over about 15 min. The reaction mixture was stirred at about−5-0° C. for about 1.5 h and then allowed to warm to rt overnight. Thereaction mixture was then filtered through a Celite® pad and washed withTHF until no further product eluted. The filtrate was concd underreduced pressure to give a brown-orange solid. The solid was trituratedand sonicated with warm petroleum ether (b.p. 30-60° C., 400 mL), cooledto rt, collected, washed with petroleum ether (b.p. 30-60° C.; 2×60 mL),and dried to give 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine(124 g, 93%, 93% purity) as a brown solid: LC/MS (Table 1, Method b)R_(t)=2.51 min; MS m/z: 270, 272 (M+H)⁺.

Step B: 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine

To a solution of 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine(3.00 g, 11.1 mmol) in DMF (60 mL) at about 0° C. was added NaH (60%dispersion in mineral oil, 0.577 g, 14.4 mmol) in three portions. Afterabout 15 min, p-toluenesulfonyl chloride (2.75 g, 14.4 mmol) was addedand the reaction was allowed to warm slowly to ambient temperature.After about 16 h, the reaction mixture was poured onto ice-cold water(120 mL) and the precipitate was collected by vacuum filtration. Thecrude solid was dissolved in DCM (15 mL) and purified by silica gelchromatography eluting with DCM to give2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (2.16 g, 52%): LC/MS (Table 1,Method c) R_(t)=1.58 min; MS m/z: 352, 354 (M+H)⁺.

Step C: (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride

A 5 L reactor was charged with 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine(98.8 g, 281 mmol), zinc dust (3.50 g, 53.3 mmol), palladium(II)trifluoroacetate (4.0 g, 12 mmol), andracemic-2-(di-t-butylphosphino)-1,1′-binapthyl (9.8 g, 24.7 mmol). Theflask was equipped with a powder addition device into which zinc cyanide(10.0 g, 157 mmol) was placed to be added at a later step. The vesselwas purged with argon for no longer than about 30 min and then argonsparged DMA (2 L) was added to the reactor. The mixture was stirred andheated to about 50° C. while maintaining an argon atmosphere. Theresulting dark brown solution was further heated to about 95° C. whileadding the zinc cyanide, from the powder addition device, portionwiseover about 15 min. Upon reaching about 95° C., the brown mixture wasstirred for about an additional 16 h. The reaction mixture was cooled toambient temperature, resulting in the precipitation of salts. Themixture was filtered through a Buchner funnel containing filter-aid andthe filter cake was washed with DMA (20 mL). A solution of the crudeproduct in DMA was added to cold (<10° C.) water (16 L) and stirred forabout 30 min. The resulting suspension was filtered and the filter cakewas rinsed again with water (1 L). The resulting wet cake was dried in avacuum oven at about 50° C. The crude solid was dissolved in DCM (1.5 L)and further dried over anhydrous MgSO₄. After filtration, the solutionwas passed through a pad of silica (140 g), washed with additionalsolvent until only predominantly impurities were detected eluting offthe pad. The solvent was removed and the crude solid was triturated withMeOH/DCM (4:1, 10 volumes of solvent per gram of crude solid) at ambienttemperature for about 5 h. The solid was filtered and washed with MeOH(300 mL). The product was dried in a vacuum oven to provide5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbonitrile (58.8 g, 70%) as awhite solid: ¹H NMR (CDCl₃) δ8.67 (s, 1H), 8.21 (d, J=4.2 Hz, 1H), 8.07(d, J=8.4 Hz, 2H), 7.34 (d, J=8.1 Hz, 2H), 6.89 (d, J=4.2 Hz, 1H), 2.42(s, 3H). A 2 L 316-stainless steel pressure reactor was charged with 5wt % Pd/C (15.4 g of 63.6 wt % water wet material, 5.6 g dry basis, 2.6mmol, Johnson Matthey A503032-5),5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbonitrile (55 g, 184 mmol), THF(1.1 L), deionized water (165 mL), HCl (37 wt % aqueous, 30 mL, 369mmol) and quinoline (1.1 mL, 9.0 mmol). The vessel was purged,pressurized, and maintained at 40 psi with hydrogen supplied from a highpressure reservoir. The mixture was vigorously agitated at about 25° C.After about 5 h the reactor was vented and purged with nitrogen toremove most of the dissolved hydrogen, and the reaction mixture wasfiltered to remove the catalyst. The reactor and catalyst cake wererinsed with THF:water (1:1, 2×40 mL). The combined filtrate and rinseswere concd and EtOH (500 mL) was added. After two additional solventswitches with EtOH (2×500 mL), the crude residue was concd under reducedpressure to give a residue (76 g) that was suspended in EtOH (550 mL)and stirred at ambient temperature for about 4 h. The solid wascollected by filtration and washed with cold EtOH (50 mL). The wet cakewas dried in a vacuum oven to provide(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride (51.2g, 82%) as a white solid: LC/MS (Table 1, Method a) R_(t)=1.44 min; MSm/z: 303 (M+H)⁺.

Step D: (R)-tert-butyl3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)piperidine-1-carboxylate

DIEA (7.7 mL, 44.3 mmol) was added to a solution of(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride (5 g,14.7 mmol) in DCM (78 mL) and the reaction was stirred at ambienttemperature for about 10 min followed by the addition of(R)—N-Boc-piperidine-3-carboxylic acid (3.38 g, 14.7 mmol,CNH-Technologies) and HATU (5.61 g, 14.7 mmol). The mixture was stirredfor about 1 h, then water (30 mL) was added, and the layers wereseparated. The organic layer was washed with saturated aqueous NaHCO₃(30 mL) and brine (30 mL), dried over anhydrous MgSO₄, filtered, andconcd under reduced pressure. The crude material was purified by silicagel chromatography eluting with a gradient of 0-5% MeOH in DCM to affordcrude (R)-tert-butyl3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)piperidine-1-carboxylate(7.58 g, 94%): LC/MS (Table 1, Method b) R_(t)=2.30 min; MS m/z: 514(M+H)⁺.

Step E: (R)-tert-butyl3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamothioyl)-piperidine-1-carboxylate

To a solution of (R)-tert-butyl3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)-piperidine-1-carboxylate(7.58 g, 13.8 mmol) in 1,4-dioxane (130 mL) was added Lawesson's reagent(3.37 g, 8.32 mmol) and the reaction mixture was heated to about 60° C.for about 2 h then cooled to ambient temperature and concd under reducedpressure. The crude residue was dissolved in EtOAc (40 mL) and washedwith saturated aqueous NaHCO₃, (3×40 mL), brine (30 mL), dried overanhydrous MgSO₄, filtered, and concd under reduced pressure. The crudematerial was purified by silica gel chromatography eluting with agradient of 0-5% MeOH in DCM to afford (R)-tert-butyl3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamothioyl)piperidine-1-carboxylate(5.6 g, 74%, UV purity 97%): LC/MS (Table 1, Method b) R_(t)=2.60 min;MS m/z: 530 (M+H)⁺.

Step F: (R)-tert-butyl3-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate

To a solution of (R)-tert-butyl3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamothioyl)-piperidine-1-carboxylate(5.61 g, 10.3 mmol) in 1,4-dioxane (96 mL) was added mercury (II)trifluoroacetate (4.38 g, 10.3 mmol). The reaction mixture was stirredat ambient temperature for about 2 h then filtered through a pad ofCelite®. The Celite® pad was rinsed with EtOAc (50 mL) and the filtratewas concd under reduced pressure. The crude residue was dissolved inEtOAc (40 mL) and the organic phase was washed with saturated aqueousNaHCO₃ (2×40 mL) and brine (30 mL), dried over anhydrous MgSO₄,filtered, and concd under reduced pressure. The crude material waspurified by silica gel chromatography eluting with a gradient of 0-5%MeOH in DCM to afford (R)-tert-butyl3-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate(4.4 g, 87%): LC/MS (Table 1, Method b) R_(t)=2.49 min; MS m/z: 496(M+H)⁺.

Step G: (R)-tert-butyl3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate

To a solution of (R)-tert-butyl3-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate(4.44 g, 8.96 mmol) in 1,4-dioxane (54 mL) was added NaOH (2 N aqueous,8.9 mL, 18 mmol), and the resulting mixture was heated at about 60° C.for about 3 h. The reaction was cooled to ambient temperature and EtOAc(30 mL) and saturated aqueous NH₄Cl (20 mL) were added. The organiclayer was separated and the aqueous layer was further extracted withEtOAc (40 mL). The combined organic layers were washed with brine (40mL), dried over anhydrous MgSO₄, filtered, and concd under reducedpressure. The material was purified by silica gel chromatography elutingwith a gradient of 0-10% MeOH in DCM to afford (R)-tert-butyl3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate(2.80 g, 92%): LC/MS (Table 1, Method b) R_(t)=1.85 min; MS m/z: 342(M+H)⁺.

Step H: (R)-1-(piperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazinehydrochloride

A round bottom flask was charged with (R)-tert-butyl3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate(2.8 g, 8.20 mmol), 1,4-dioxane (24 mL) and HCl (4 N in 1,4-dioxane, 6.2mL, 24.6 mmol). The reaction mixture was heated at about 60° C. forabout 18 h. The reaction mixture was cooled to ambient temperature andEt₂O (40 mL) was added and the mixture was stirred for about 15 min. Thesolid was collected by vacuum filtration, while washed with Et₂O (50mL), and then dried in a vacuum oven at about 60° C. to afford(R)-1-(piperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazinehydrochloride (2.4 g, 94%) as an off-white solid: LC/MS (Table 1, Methodb) R_(t)=0.81 min; MS m/z 242 (M+H)⁺.

Step I: (R)-cyclopentyl3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate

To a solution of(R)-1-(piperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazinehydrochloride (0.06 g, 0.19 mmol) in THF (1 mL) was added TEA (0.08 mL,0.57 mmol) and the reaction was stirred at ambient temperature for about10 min. To the reaction mixture was added cyclopentyl chloroformate(0.02 mL, 0.15 mmol, Waterstone) and the mixture was stirred at about45° C. for about 18 h. The reaction mixture was cooled to ambienttemperature and concd under reduced pressure. The crude material wasdissolved in DCM (5 mL) and washed with water (5 mL). The organic layerwas separated and the aqueous layer was back extracted with DCM (2 mL).The combined organic extracts were dried over anhydrous MgSO₄, filtered,and concd under reduced pressure. The material was purified by silicagel chromatography eluting with a gradient of 0-5% MeOH in DCM to afford(R)-cyclopentyl3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate(0.015 g, 21%): LC/MS (Table 1, Method b) R_(t)=1.87 min; MS m/z: 354(M+H)⁺.

Example #12(E)-3-(1-cyclohexyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)acrylicacid

Step A: (E)-ethyl3-(1-cyclohexyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)acrylate

To a solution of3-bromo-1-cyclohexyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine(0.026 g, 0.056 mmol, Preparation #MM.1) and PdCl2(dppf).DCM adduct(0.005 g, 0.006 mmol) in THF (1 mL) was added (E)-ethyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (0.052 g, 0.23mmol) and Na₂CO₃ (0.021 g, 0.20 mmol) followed by water (0.25 mL). Thereaction mixture was heated to about 65° C. After about 15 h, thereaction mixture was cooled to ambient temperature and directly purifiedby chromatography on silica gel (12 g) eluting with 20-80% EtOAc:DCM(1:1) in heptane to provide (E)-ethyl3-(1-cyclohexyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)acrylate(0.045 g, 70%) as a yellow solid: LC/MS (Table 1, Method a) R_(t)=3.15min; MS m/z: 493 (M+H)⁺.

Step B:(E)-3-(1-cyclohexyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)acrylicacid

To a solution of (E)-ethyl3-(1-cyclohexyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)acrylate(0.064 g, 0.13 mmol) in 1,4-dioxane (5 mL) was added NaOH (2 N aqueous,1.30 mL, 2.60 mmol). The reaction mixture was heated to about 65° C.After about 15 h, the reaction mixture was cooled to ambient temperatureand the pH of the reaction mixture was adjusted to about pH 1 withconcentrated HCl. The mixture was partially concd in vacuo to remove the1,4-dioxane and the resulting yellow solid was collected by filtrationand dried in vacuo to provide(E)-3-(1-cyclohexyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)acrylicacid (0.015 g, 37.2%): LC/MS (Table 1, Method a) R_(t)=1.85 min; MS m/z:311 (M+H)⁺.

Example #133-(1-cyclohexyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)propanoicacid

To solution of ethyl3-(1-cyclohexyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)propanoate(0.031 g, 0.063 mmol, prepared using W from Example #12 Step A) in1,4-dioxane (3 mL) was added NaOH (2 N aqueous, 1.57 mL, 3.13 mmol). Thereaction mixture was heated to about 65° C. After about 2 h, thereaction mixture was cooled to ambient temperature and the pH of themixture was adjusted to about 1 with 1 N aqueous HCl. The reactionmixture was concd in vacuo and purified by chromatography on silica gel(12 g) eluting with 2-10% MeOH in DCM to provide3-(1-cyclohexyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)propanoicacid (0.005 g, 26%) as a tan solid: LC/MS (Table 1, Method a) R_(t)=1.68min; MS m/z: 313 (M+H)⁺.

Example #14*N-((1S,3R,4S)-3-ethyl-4-(3-(3-hydroxypropyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide

To a solution ofN-((1S,3S,4R)-3-(3-allyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-ethylcyclopentyl)cyclopropanesulfonamide(0.090 g, 0.16 mmol, prepared using H with Preparation #12, Preparation#Z.1, HATU and DIEA, and Q with Lawesson's reagent and mercury (II)trifluoroacetate) in THF (3 mL) at about 0° C. was added BH₃DMS (2 M inTHF, 0.040 mL, 0.079 mmol). After about 2 h, additional BH₃DMS (2 M inTHF, 0.040 mL, 0.079 mmol) was added to the reaction mixture. Afterabout 6 h total, a premixed solution of H₂O₂ (30% aqueous, 0.324 mL,3.17 mmol) and NaOH (2 N aqueous, 0.793 mL, 1.58 mmol) was added to thereaction mixture. After stirring for about 15 h, EtOAc (20 mL) and water(20 mL) were added to the reaction mixture. The organic layer wasseparated, washed with brine (20 mL), and concd in vacuo. The cruderesidue was purified by chromatography on silica gel (12 g) eluting withEtOAc to provideN-((1S,3R,4S)-3-ethyl-4-(3-(3-hydroxypropyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide(0.025 g, 37%) as a white solid: LC/MS (Table 1, Method a) R_(t)=1.70min; MS m/z: 432 (M+H)⁺.

Example #15N-(1-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrrolidin-3-yl)cyclopropanesulfonamide

To a solution of tert-butyl1-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrrolidin-3-ylcarbamate(0.175 g, 0.511 mmol, Example #D.1.42) in DCM (10 mL) was added HCl (4 Nin 1,4-dioxane, 1.28 mL, 5.11 mmol). After about 4 h at ambienttemperature, the reaction mixture was concd in vacuo. The residue wassuspended in DCM (10 mL) and DIEA (0.446 mL, 2.56 mmol) was added to thereaction mixture resulting in a nearly homogeneous mixture. To themixture was added cyclopropanesulfonyl chloride (0.079 g, 0.56 mmol).After about 2 h at ambient temperature, additional cyclopropane-sulfonylchloride (0.079 g, 0.56 mmol) was added. After about 6 h at ambienttemperature, saturated aqueous NaHCO₃ (10 mL) was added to the reactionmixture. The organic layer was separated and the aqueous layer wasextracted with DCM (3×10 mL). The combined organic layers were concd invacuo and purified by chromatography on silica gel (40 g) eluting with50-90% MeCN in DCM to provideN-(1-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrrolidin-3-yl)cyclopropane-sulfonamide(0.125 g, 70%) as a tan solid: LC/MS (Table 1, Method a) R_(t)=1.42 min;MS m/z: 347 (M+H)⁺.

Example #161-cyclohexyl-3-phenyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine

To a solution of3-bromo-1-cyclohexyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine(0.27 g, 0.056 mmol, Preparation #MM.1) and PdCl2(dppf).DCM adduct(0.0046 g, 0.0056 mmol) in THF (1 mL) was added a solution ofphenylboronic acid (0.12 g, 0.098 mmol) and Na₂CO₃ (0.009 g, 0.084 mmol)in water (0.25 mL). The reaction mixture was heated to about 60° C.After about 6 h, the reaction mixture was cooled to ambient temperatureand was diluted with EtOAc (5 mL) and brine (5 mL). The organic layerwas separated and concd in vacuo. The residue was dissolved in1,4-dioxane (5 mL) and NaOH (2 N aqueous, 1 mL) was added. The reactionmixture was heated to about 65° C. After about 15 h, the reactionmixture was cooled to ambient temperature and HCl (1 N aqueous, 3 mL)and EtOAc (5 mL) were added. The organic layer was separated, concd invacuo, and the residue was purified by chromatography on silica gel (12g) eluting with 20-80% EtOAc in DCM to provide1-cyclohexyl-3-phenyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (0.005 g,28%) as a solid: LC/MS (Table 1, Method a) R_(t)=2.75 min; MS m/z: 317(M+H)⁺.

Example #17*N-((1S,3R,4S)-3-ethyl-4-(3-(hydroxymethyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide

To a solution ofN-((1S,3S,4R)-3-(3-allyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-ethylcyclopentyl)cyclopropanesulfonamide(0.17 g, 0.299 mmol, prepared using H with Preparation #12, Preparation#Z.1, HATU and DIEA, and Q with Lawesson's reagent and mercury (II)trifluoroacetate) in 1,4-dioxane (5 mL) and water (1.7 mL) was addedsodium periodate (0.26 g, 1.2 mmol) followed by osmium tetroxide (4 wt %in water, 0.117 mL, 0.015 mmol). After about 48 h at ambienttemperature, the reaction mixture was diluted with water (about 50 mL)and EtOAc (30 mL). The organic layer was separated, dried over anhydrousNa₂SO₄, filtered, and concd in vacuo. The crude aldehyde was dissolvedin EtOH (10 mL) and NaBH₄ (0.023 g, 0.599 mmol) was added to thereaction mixture. After about 2 h at ambient temperature, HCl (1 Naqueous, about 3 mL) was added. After stirring for about 30 min, thereaction mixture was concd in vacuo. The residue was partitioned betweenEtOAc (30 mL) and saturated aqueous NaHCO₃ (30 mL). The organic layerwas separated, dried over anhydrous Na₂SO₄, filtered, and concd invacuo. The crude alcohol was dissolved in 1,4-dioxane (10 mL) and NaOH(2 N aqueous, 1.5 mL, 2.99 mmol) was added. The reaction mixture washeated to about 80° C. After about 4 h, the reaction mixture was cooledto ambient temperature and diluted with EtOAc (30 mL) and saturatedaqueous NH₄Cl (30 mL). The organic layer was separated, concd in vacuo,and purified by chromatography on silica gel eluting with 10-50% MeCN inDCM to provideN-((1S,3R,4S)-3-ethyl-4-(3-(hydroxymethyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide(0.007 g, 6%) as a yellow solid: LC/MS (Table 1, Method a) R_(t)=1.59min; MS m/z: 404 (M+H)⁺.

Example #18*N-((1S,3R,4S)-3-ethyl-4-(3-(2-hydroxyethyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide

To a solution ofN-((1S,3S,4R)-3-(3-allyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-ethylcyclopentyl)cyclopropanesulfonamide(0.170 g, 0.299 mmol, prepared using H with Preparation #12, Preparation#Z.1, HATU and DIEA, Q with Lawesson's reagent and mercury (II)trifluoroactate) in 1,4-dioxane (5 mL) and water (1.67 mL) was addedsodium periodate (0.26 g, 1.198 mmol) followed by osmium tetroxide (4 wt% in water, 0.12 mL, 0.015 mmol). After about 4 h at ambienttemperature, the reaction mixture was diluted with water (about 50 mL)and the resulting precipitate was collected by filtration. The crudealdehyde was dissolved in EtOH (10 mL) and NaBH₄ (0.023 g, 0.60 mmol)was added to the reaction mixture. After about 2 h at ambienttemperature, HCl (1 N aqueous, about 3 mL) was added to the reactionmixture. After stirring for about 30 min, the reaction mixture was concdin vacuo. The residue was partitioned between EtOAc (20 mL) andsaturated aqueous NaHCO₃ (20 mL). The organic layer was separated, driedover anhydrous Na₂SO₄, filtered, and concd in vacuo. The crude alcoholwas dissolved in 1,4-dioxane (10 mL) and NaOH (2 N aqueous, 1.50 mL,2.99 mmol) was added. The reaction mixture was heated to about 80° C.After about 4 h, the reaction mixture was cooled to ambient temperatureand diluted with EtOAc (30 mL) and saturated aqueous NH₄Cl (30 mL). Theorganic layer was separated, concd in vacuo, and purified bychromatography on silica gel (40 g) eluting with 5% MeOH in DCM toprovideN-((1S,3R,4S)-3-ethyl-4-(3-(2-hydroxyethyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide(0.025 g, 20%) as a yellow solid: LC/MS (Table 1, Method a) R_(t)=1.67min; MS m/z: 418 (M+H)⁺.

Example #19*N-((1S,3R,4S)-3-ethyl-4-(3-(2-(methylsulfonyl)ethyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide

To a solution ofN-((1S,3S,4R)-3-(3-allyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-ethylcyclopentyl)cyclopropanesulfonamide(0.28 g, 0.48 mmol, prepared using H with Preparation #12, Preparation#Z.1, HATU and DIEA, Q with Lawesson's reagent and mercury (II)trifluoroacetate) in 1,4-dioxane (5 mL) and water (1.5 mL) was addedsodium periodate (0.21 g, 0.97 mmol) followed by osmium tetroxide (4 wt% in water, 0.19 mL, 0.024 mmol). After about 4 h, the reaction mixturewas diluted with DCM (10 mL) and water (10 mL), the organic layer wasseparated and concd in vacuo. The crude aldehyde was dissolved in EtOH(5 mL) and NaBH₄ (0.18 g, 4.8 mmol) was added to the reaction mixture.After about 4 h, HCl (1 N aqueous, 10 mL) and DCM (20 mL) were added tothe reaction mixture. The organic layer was separated and concd invacuo. The residue was purified by silica gel chromatography elutingwith EtOAc in DCM to give crude alcohol (0.061 g). To a solution of thecrude alcohol in DCM (1 mL) was added DIEA (0.047 mL, 0.27 mmol)followed by methanesulfonyl chloride (0.0092 mL, 0.12 mmol). After about2 h, the reaction mixture was diluted with DCM (10 mL) and saturatedaqueous NaHCO₃ (10 mL). The organic layer was separated, concd in vacuo,and diluted with DMF (1.0 mL). Sodium methanethiolate (0.075 g, 1.1mmol) was added to the reaction mixture. After stirring at ambienttemperature for about 15 h, the reaction mixture was heated to about 50°C. After about 4 h, the reaction mixture was cooled to ambienttemperature and diluted with DCM (10 mL) and saturated aqueous NaHCO₃(10 mL). The organic layer was separated, concd in vacuo, and purifiedby chromatography on silica gel (40 g) eluting with 20-80% MeCN in DCM.The fractions containing the thioether were combined and concd in vacuo.The crude thioether was dissolved in DCM (1 mL) and treated with OXONE®tetrabutylammonium salt (0.114 g, 0.320 mmol). After about 4 h, thereaction mixture was diluted with DMSO (1 mL) and partially concd invacuo to remove DCM. The crude mixture was purified by RP-HPLC (Table 1,Method k). The fractions containing the desired sulfone were combinedand concd in vacuo. The residue was further purified by chromatographyon silica gel (12 g) eluting with 5% MeOH in DCM to provideN-((1S,3R,4S)-3-ethyl-4-(3-(2-(methylsulfonyl)ethyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide(0.002 g, 1.4%) as a solid: LC/MS (Table 1, Method a) R_(t)=1.82 min; MSm/z: 480 (M+H)⁺.

Example #20(cis-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methanol

To a solution of5-((cis-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methoxy)pyrazine-2-carbonitrile(0.145 g, 0.267 mmol, prepared using P from Preparation #11 with LAH, JJwith 5-chloropyrazine-2-carbonitrile [ArkPharm], TT with TFA, A fromExample #1 Step D, HATU, and TEA, B with TEA) in 1,4-dioxane (2.7 mL)was added Na₂CO₃ (2 N aqueous, 2.7 mL). The reaction was heated at about50° C. for about 16 h. EtOH (2 mL) was added to the reaction mixture.The reaction was kept at about 50° C. for about 16 h and then cooled toambient temperature. The material was purified by RP-HPLC (Table 1,Method d) to give(cis-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methanol(0.024 g, 31%) as the product: LC/MS (Table 1, Method b) R_(t)=1.63 min;MS m/z 286 (M+H)⁺.

Example #21 1-cyclohexyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine

Step A: 4-chloro-3-iodo-5-nitropyridin-2-amine

A solution of 4-chloro-3-iodopyridin-2-amine (4.00 g, 15.7 mmol, Adesis)in concd H₂SO₄ (45 mL) was cooled to about 0° C. in an ice bath.Potassium nitrate (3.50 g, 34.6 mmol) was added in four portions overabout 10 min. The resulting solution was stirred at about 0° C. forabout 1 h, then at ambient temperature for about 4 h. The reactionmixture was slowly poured over crushed ice (total volume 1 L) resultingin formation of a solid that was collected by vacuum filtration anddried under vacuum to give 4-chloro-3-iodo-5-nitropyridin-2-amine (2.2g, 47%) as a yellow solid: LC/MS (Table 1, Method c) R_(t)=1.48 min; MSm/z 298 (M−H)⁻.

Step B: 4-chloro-5-nitro-3-((trimethylsilyl)ethynyl)pyridin-2-amine

To a solution of 4-chloro-3-iodo-5-nitropyridin-2-amine (5.30 g, 17.7mmol) in THF (90 mL) was added TEA (15.0 mL, 108 mmol). The reactionmixture was degassed and purged with nitrogen 3 times.Bis(triphenylphosphine)-palladium(II)dichloride (0.62 g, 0.88 mmol,Strem), copper(I) iodide (0.17 g, 0.89 mmol), andtrimethylsilylacetylene (5.4 mL, 39 mmol) were added to the reactionmixture, degassed, and purged 3 times with nitrogen. The reaction washeated at about 60° C. for about 16 h. The reaction mixture was cooledto ambient temperature. The reaction mixture was filtered and washedwith THF (200 mL). The filtrate was concd under reduced pressure. DCM(100 mL) was added to the residue and the precipitate that formed wasfiltered and collected to give4-chloro-5-nitro-3-((trimethylsilyl)ethynyl)pyridin-2-amine (0.77 g).The remaining filtrate was concd under reduced pressure and the crudematerial was purified by flash chromatography on silica gel eluting witha gradient of 0-100% EtOAc in DCM. The purified material was combinedwith the 0.77 g of precipitate to afford4-chloro-5-nitro-3-((trimethylsilyl)ethynyl)pyridin-2-amine (2.22 g,47%) as a yellow solid: LC/MS (Table 1, Method c) R_(t)=1.62 min; MS m/z268 (M−H)⁻.

Step C: 4-chloro-3-ethynyl-5-nitropyridin-2-amine

To a solution of4-chloro-5-nitro-3-((trimethylsilyl)ethynyl)pyridin-2-amine (2.36 g,8.76 mmol) in DMF (30 mL) was added potassium fluoride on alumina (40 wt%, 3.2 g, 22 mmol). The suspension was stirred at about ambienttemperature for about 2 h. Activated charcoal (0.23 g) was added and thesuspension was filtered though Celite®, washed with DMF (200 mL). Thesolvent was removed under reduced pressure and the residue wastriturated with petroleum ether (50 mL, b.p. 30-60° C.). The solid wasfiltered, washed with petroleum ether (4×25 mL, b.p. 30-60° C.), anddried in vacuo to give 4-chloro-3-ethynyl-5-nitropyridin-2-amine (2.12g, 89%) as a brown solid: LC/MS (Table 1, Method c) R_(t)=1.32 min; MSm/z 196 (M−H)⁻.

Step D: 4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine

To a solution of 4-chloro-3-ethynyl-5-nitropyridin-2-amine (0.16 g, 0.81mmol) in DMF (3 mL) was added chloro(1,5-cyclooctadiene)rhodium (I)dimer (0.02 g, 0.04 mmol) and tris(4-fluorophenyl)phosphine (0.128 g,0.405 mmol). The reaction mixture was degassed by bubbling argon for 15min. The reaction mixture was heated at about 80° C. for about 45 min.The solvent was removed under reduced pressure and the residue wassuspended in ether (10 mL). The precipitate was collected by filtrationand dried to give 4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (0.132 g,83%, contains approximately 6% mol of DMF and approximately 3% mol oftris(4-fluorophenyl)phosphine) as a brown solid: LC/MS (Table 1, Methoda) R_(t)=2.05 min; MS m/z 198 (M+H)⁺.

Step E: N-cyclohexyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-amine

To a solution of 4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (0.182 g,0.921 mmol) in DMF (5 mL) was added cyclohexylamine (0.55 g, 5.5 mmol).The reaction mixture was stirred at ambient temperature for about 2 h.The solvent was removed under reduced pressure and EtOAc (100 mL) andwater (20 mL) were added. The layers were separated and the organiclayer was washed with water (3×25 mL) and brine (20 mL), dried overanhydrous MgSO₄, filtered, and concd to giveN-cyclohexyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-amine (0.20, 57%) as abrown residue: LC/MS (Table 1, Method c) R_(t)=1.53 min; MS m/z 261(M+H)⁺.

Step F: N-cyclohexyl-1H-pyrrolo[2,3-b]pyridine-4,5-diamine

To a solution of N-cyclohexyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-amine(0.15 g, 0.57 mmol) in EtOH (10 mL) was added tin (II) chloridedihydrate (0.65 g, 2.9 mmol). The reaction mixture was heated at about55° C. for about 1 h. The solvent was removed under reduced pressure andEtOAc (75 mL) and saturated aqueous NaHCO₃ (25 mL) were added. The solidthat formed was collected by vacuum filtration, washed with EtOAc (25mL), and discarded. The filtrate was washed with saturated aqueousNaHCO₃ (3×20 mL), dried over anhydrous MgSO₄, filtered, and concd togive N-cyclohexyl-1H-pyrrolo[2,3-b]pyridine-4,5-diamine (0.107 g, 87%)as a brown residue: LC/MS (Table 1, Method c) R_(t)=1.21 min; MS m/z 231(M+H)⁺.

Step G: 1-cyclohexyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine

To a solution of N-cyclohexyl-1H-pyrrolo[2,3-b]pyridine-4,5-diamine(0.084 g, 0.36 mmol) in triethyl orthoformate (1 mL, 6 mmol) was addedp-toluenesulfonic acid monohydrate (0.002 g, 0.011 mmol). The reactionmixture was heated at about 80° C. for about 1 h. p-Toluenesulfonic acidmonohydrate (0.002 g, 0.011 mmol) was added and the reaction mixture wasstirred at about 80° C. After about 1 h, p-toluenesulfonic acidmonohydrate (0.002 g, 0.011 mmol) was added and the reaction mixture wasstirred at about 80° C. for about 2 h. The reaction mixture was cooledto ambient temperature and concd under reduced pressure. The reactionwas purified by RP-HPLC (Table 1, Method m) to give1-cyclohexyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine (0.002 g,2%) as a brown solid: LC/MS (Table 1, Method a) R_(t)=1.90 min; MS m/z241 (M+H)⁺.

Example #221-((1S,2R,4S)-2-ethyl-4-(tetrahydro-2H-pyran-4-yloxy)cyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine

Step A: ethyl 2-ethyl-4-oxocyclopent-2-enecarboxylate

In a 5 L round bottom flask, sodium4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-dienolate(316 g, 1205 mmol, [Example #1, step E]), KCl (126 g, 1687 mmol), andAcOH (241 mL, 4218 mmol, JT Baker) in toluene (1850 mL) and water (130mL) were heated at reflux for about 6 h. The reaction mixture wasallowed to cool to ambient temperature for about 16 h. The reactionmixture was added dropwise to an aqueous solution of NaHCO₃ (3.5 L, 8%).The aqueous layer was extracted with MTBE (2×1.5 L). The combinedorganic layers were washed with brine (1 L), dried over anhydrous MgSO₄,filtered, and concd under reduced pressure. The crude material waspurified by vacuum distillation (80-98° C., 0.6 mmHg) to give ethyl2-ethyl-4-oxocyclopent-2-enecarboxylate (160.4 g, 69%): ¹H NMR (400 MHz,CDCl₃) δ 6.05-6.02 (m, 1H), 4.28-4.14 (m, 2H), 3.75 (m, J=0.9, 1.8, 3.8,6.7, 1H), 2.69 (dd, J=3.1, 18.4, 1H), 2.61 (dd, J=6.9, 18.4, 1H), 2.52(dq, J=7.4, 24.2, 1H), 2.40 (dq, J=7.4, 16.1, 1H), 1.30 (t, J=7.2, 3H),1.21 (t, J=7.4, 3H).

Step B: ethyl 2-ethyl-4-oxocyclopentanecarboxylate

In a 1 L round-bottomed jacketed flask, copper(I) chloride (0.679 g,6.86 mmol), (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (4.27 g,6.86 mmol), and sodium tert-butoxide (0.6.59 g, 6.86 mmol) in toluene(250 mL) were added to give a brown solution. The mixture was stirred atambient temperature for 15 min after which the solution became brown.The solution was cooled to about 5° C. and polymethylhydrosiloxane(18.29 mL, 274 mmol) was added and the reaction mixture was stirred atabout 5° C. for about 40 min. The solution was cooled to about −15° C.and a solution of ethyl 2-ethyl-4-oxocyclopent-2-enecarboxylate (25.00g, 137 mmol) and tert-butyl alcohol (69.9 mL, 741 mmol) in toluene (250mL) was added in one portion and the reaction stirred at about −15° C.for about 120 h. The reaction mixture was quenched by the addition of1:1 ethanol/toluene (350 mL) and Celite® 545 (25 g). The mixture wasstirred for about 3 h and allowed to warm to ambient temperature. Thereaction mixture was concd in vacuo, chasing with heptane. Heptane (350mL) was added to the residue and solids were removed by filtration. Thefiltrate was concd in vacuo and the crude product was purified by silicagel chromatography using a gradient of 10 to 50% EtOAc in heptane over 7column volumes to give ethyl 2-ethyl-4-oxocyclopentanecarboxylate as ascalemic mixture of diastereomers, predominantly (1S,2R)-ethyl2-ethyl-4-oxocyclopentanecarboxylate (13.68 g, 54%) as a colorless oil.¹H NMR (400 MHz, CDCl₃) δ 4.17 (qd, J=7.1, 1.5, 2H), 3.25-3.18 (m, 1H),2.55 (m, J=4.7, 3.5, 1.7, 1H), 2.46-2.29 (m, 3H), 2.21 (m, J=11.6, 9.8,1.3, 1H), 1.53 (m, J=14.8, 7.4, 6.1, 1H), 1.42-1.30 (m, 1H), 1.27 (t,J=7.1, 3H), 0.98 (t, J=7.4, 3H).

Step C: (ethyl 2-ethyl-4-hydroxycyclopentanecarboxylate

To a solution of ethyl 2-ethyl-4-oxocyclopentanecarboxylate (12.82 g,69.6 mmol, 86% ee, predominantly 1S,2R) in MeOH (183 mL) was addedsodium borohydride (3.29 g, 87 mmol) portion-wise. The suspension wasstirred at ambient temperature for about 16 h. Saturated aqueous NH₄Cl(200 mL) was added and the reaction was stirred for about 3 h. The whiteprecipitate that formed was filtered and washed with Et₂O (100 mL). Thefiltrate was poured into Et₂O (300 mL). The solid was filtered andwashed with Et₂O (50 mL). The layers were separated and the aqueouslayer was extracted with Et₂O (2×150 mL). The combined organic layerswere washed with brine (2×150 mL), dried over anhydrous MgSO₄, filteredand concd under reduce pressure (keeping bath temperature about 25° C.and vacuum >50 psi) to give a crude product as a thick light yellow oil.The oil was washed with pentane (5×80 mL). The combined pentane layerswere dried over anhydrous MgSO₄, filtered and concd to give an oil whichwas purified by silica gel chromatography using 1:1 EtOAc:pentane togive ethyl 2-ethyl-4-hydroxycyclopentanecarboxylate as a scalemicmixture of diastereomers predominantly (1S,2R,4S)-ethyl2-ethyl-4-hydroxycyclopentanecarboxylate (12.38 g, 96%) as a clear oil;¹H NMR (400 MHz, CDCl₃) δ 4.34-4.25 (m, 1H), 4.23-4.09 (m, 2H),3.43-3.17 (m, 1H), 2.88 (td, J=7.1, 2.2, 1H), 2.40 (dt, J=14.0, 7.8,1H), 2.09-1.91 (m, 3H), 1.33-1.24 (m, 4H), 0.95 (t, J=7.4, 3H).

Step D: (ethyl4-(tert-butyldimethylsilyloxy)-2-ethylcyclopentanecarboxylate

To a solution of ethyl 2-ethyl-4-hydroxycyclopentanecarboxylate (10.0 g,53 7 mmol) in DMF (18 mL) was added TBDMS-Cl (9.72 g, 64.5 mmol) andimidazole (9.15 g, 134 mmol). The reaction mixture was stirred atambient temperature for about 3 h. Heptane (50 mL) was added to thereaction and the layers were separated. The bottom layer was extractedwith heptane (2×30 mL). The combined organic extracts were washed withwater (2×30 mL), brine (30 mL), dried over anhydrous MgSO₄, filtered andconcd to give ethyl4-(tert-butyldimethylsilyloxy)-2-ethylcyclopentanecarboxylate (15.87 g,52 8 mmol, 98%) as a colorless oil; ¹H NMR (400 MHz, CDCl₃) δ 4.13 (m,3H), 2.79 (m, 1H), 2.09 (m, 1H), 1.99 (m, 3H), 1.50-1.24 (m, 6H), 0.89(m, 12H), 0.05 (s, 6H).

Step E: ethyl2-ethyl-4-(tetrahydro-2H-pyran-4-yloxy)cyclopentanecarboxylate

To a solution of ethyl4-(tert-butyldimethylsilyloxy)-2-ethylcyclopentanecarboxylate (0.100 g,0.333 mmol) in MeCN (2.2 mL) was added triethylsilane (0.080 mL, 0.499mmol) and bismuth(III) bromide (0.010 g, 0.022 mmol). The reactionmixture was stirred at ambient temperature for about 1 min followed bydropwise addition of dihydro-2H-pyran-4(3H)-one (0.050 g, 0.499 mmol).The reaction mixture was stirred at ambient temperature for about 15min. The reaction was filtered through an Acrodisc® and the solvent wasremoved under reduced pressure. To a solution of ethyl4-(tert-butyldimethylsilyloxy)-2-ethylcyclopentanecarboxylate (0.200 g,0.666 mmol) in MeCN (4.5 mL) was added triethylsilane (0.160 mL, 1.00mmol) and bismuth(III) bromide (0.020 g, 0.045 mmol). The reactionmixture was stirred at ambient temperature for about 1 min followed bydropwise addition of dihydro-2H-pyran-4(3H)-one (0.100 g, 0.998 mmol).The reaction mixture was stirred at ambient temperature for about 15min. The reaction was filtered through an Acrodisc® and the solvent wasremoved under reduced pressure. The residues were dissolved in DCM (2mL) each, combined, and the crude material was purified by silica gelchromatography using a gradient of 10-100% EtOAc in heptane to giveethyl 2-ethyl-4-(tetrahydro-2H-pyran-4-yloxy)cyclopentanecarboxylate(0.253 g, 98%) as a colorless oil; ¹H NMR (400 MHz, CDCl₃) δ 4.13 (q,J=7.1, 2H), 4.05-3.98 (m, 1H), 3.98-3.88 (m, 2H), 3.58-3.47 (m, 1H),3.46-3.36 (m, 2H), 2.80 (q, J=8.5, 1H), 2.16 (dt, J=13.3, 7.7, 1H),2.09-1.93 (m, 3H), 1.90-1.81 (m, 2H), 1.62-1.49 (m, 3H), 1.43 (ddd,J=11.1, 7.4, 5.2, 1H), 1.33-1.22 (m, 4H), 0.92-0.83 (m, 3H).

Step F: 2-ethyl-4-(tetrahydro-2H-pyran-4-yloxy)cyclopentanecarboxylicacid

To a solution of ethyl2-ethyl-4-(tetrahydro-2H-pyran-4-yloxy)cyclopentanecarboxylic acid(0.250 g, 0.925 mmol) in p-dioxane (15 mL) was added aqueous NaOH (1 M,5.00 mL, 5.00 mmol) to give a colorless solution. The reaction washeated at about 70° C. for about 8 h. The reaction mixture was cooled toambient temperature. The solvent was removed under reduced pressure. Thesolution was diluted with Et₂O (30 mL). The layers were separated andthe aqueous layer was extracted with Et₂O (30 mL). The organic layer wasset aside. The aqueous layer was acidified with 5 N HCl (2 mL) to aboutpH 2. The solution was diluted with Et₂O (30 mL). The layers wereseparated and the aqueous layer was extracted with Et₂O (3×30 mL). Thecombined organic extracts were dried over anhydrous MgSO₄, filtered andconcd under reduced pressure to give2-ethyl-4-(tetrahydro-2H-pyran-4-yloxy)cyclopentanecarboxylic acidcontaining 6 mol % of 1,4-dioxane as an excepient (0.194 g, 85%) as acolorless oil; LC/MS (Table 1, Method b) R_(t)=1.71 min; MS m/z: 243(M+H)⁺.

Step G:2-ethyl-4-(tetrahydro-2H-pyran-4-yloxy)-N′-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)cyclopentanecarbohydrazide

To a solution of 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (0.233g, 0.767 mmol, WO2009152133 Preparation #9) and2-ethyl-4-(tetrahydro-2H-pyran-4-yloxy)cyclopentanecarboxylic acid(0.190 g, 0.767 mmol) in DCM (8.00 mL) was added HATU (0.350 g, 0.920mmol, Novabiochem) and TEA (0.43 mL, 3.07 mmol). The resultingsuspension was stirred at ambient temperature for about 4 h. Thereaction was partitioned between DCM (50 mL) and water (25 mL) and thelayers were separated. The organic layer was washed with water (2×25 mL)and brine (30 mL), dried over anhydrous MgSO₄, filtered, and concd togive a brown residue. The crude material was purified by silica gelchromatography using a gradient of 1-10% MeOH in DCM to give2-ethyl-4-(tetrahydro-2H-pyran-4-yloxy)-N′-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)cyclopentanecarbohydrazide(0.300 g, 74%); LC/MS (Table 1, Method b) R_(t)=2.20 min; MS m/z: 528(M+H)⁺.

Step H:1-(2-ethyl-4-(tetrahydro-2H-pyran-4-yloxy)cyclopentyl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine

To a solution of2-ethyl-4-(tetrahydro-2H-pyran-4-yloxy)-N-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)cyclopentanecarbohydrazide(0.150 g, 0.284 mmol) in p-dioxane (5.00 mL) was added DIEA (0.200 mL,1.146 mmol) and thionyl chloride (0.031 mL, 0.426 mmol). The reactionmixture was heated at about 80° C. for about 1 h, then cooled to ambienttemperature. The reaction mixture was diluted with EtOAc (50 mL), washedwith H₂O (3×25 mL) and brine (2×25 mL). The aqueous layers were backextracted with EtOAc (2×30 mL). The combined organic layers were driedwith anhydrous MgSO₄, filtered and concd to give1-(2-ethyl-4-(tetrahydro-2H-pyran-4-yloxy)cyclopentyl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine(0.145 g, 100%); LC/MS (Table 1, Method b) R_(t)=2.26 min; MS m/z: 510(M+H)⁺.

Step I:1-((1S,2R,4S)-2-ethyl-4-(tetrahydro-2H-pyran-4-yloxy)cyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine

To a solution of1-(2-ethyl-4-(tetrahydro-2H-pyran-4-yloxy)cyclopentyl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine(0.145 g, 0.285 mmol) in p-dioxane (6.00 mL) was added an aqueoussolution of NaOH (1 N, 1.50 mL, 1.50 mmol). The reaction mixture wasstirred at about 55° C. for about 45 min, then cooled to ambienttemperature. The reaction mixture was acidified to about pH 2 by theaddition of aqueous HCl (1 N, 6 mL). The aqueous layer was extractedwith DCM (3×20 mL). The combined organic layers were dried overanhydrous MgSO₄, filtered and concd to give a brown residue. The crudematerial was purified by silica gel chromatography using a gradient of1-10% MeOH in DCM. The stereoisomers were separated using AA (Table 2,Method 32, R_(t)=15.5 min, or =negative) to give1-((1S,2R,4S)-2-ethyl-4-(tetrahydro-2H-pyran-4-yloxy)cyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine(0.048 g, 48%): LC/MS (Table 1, Method a) R_(t)=1.70 min; MS m/z: 356(M+H)⁺.

Example #23N-((1S,3R,4S)-3-ethyl-4-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclopentyl)cyclopropanesulfonamide

Step A: 4-chloro-3-iodo-5-nitropyridin-2-amine

A solution of 4-chloro-3-iodopyridin-2-amine (0.25 g, 0.982 mmol, BoaPharma) in concd H₂SO₄ (1.95 mL) was cooled to about 0° C. before theportion wise addition of potassium nitrate (0.21 g, 2.2 mmol) over 10min. The reaction was stirred for about 4 h at about 0° C. The reactionmixture was slowly pipetted over a solution of ammonium hydroxide andcrushed ice (10 mL) in an ice bath. The pH of the reaction wasmaintained above 9 by the incremental addition of ammonium hydroxide.The resulting precipitate is filtered and dried to afford4-chloro-3-iodo-5-nitropyridin-2-amine (0.085 g, 29%) as a green-tintedsolid LC/MS (Table 1, Method n) R_(t)=0.64 min; MS m/z: 298 (M−H)⁻.

Step B: 4-chloro-5-nitro-3-((trimethylsilyl)ethynyl)pyridin-2-amine

To a solution of 4-chloro-3-iodo-5-nitropyridin-2-amine (5.30 g, 17 7mmol) in THF (90 mL) was added TEA (15.0 mL, 108 mmol). The reactionmixture was degassed and purged with nitrogen 3 times.Bis(triphenylphosphine)-palladium(II)dichloride (0.62 g, 0.88 mmol,Strem), copper(I) iodide (0.17 g, 0.89 mmol), andtrimethylsilylacetylene (5.4 mL, 39 mmol) were added to the reactionmixture, degassed, and purged 3 times with nitrogen. The reaction washeated at about 60° C. for about 16 h. The reaction mixture was cooledto ambient temperature. The reaction mixture was filtered and washedwith THF (200 mL). The filtrate was concd under reduced pressure. DCM(100 mL) was added to the residue and the precipitate that formed wasfiltered and collected to give4-chloro-5-nitro-3-((trimethylsilyl)ethynyl)pyridin-2-amine (0.77 g).The remaining filtrate was concd under reduced pressure and the crudematerial was purified by flash chromatography on silica gel eluting witha gradient of 0-100% EtOAc in DCM. The purified material was combinedwith the 0.77 g of precipitate to afford4-chloro-5-nitro-3-((trimethylsilyl)ethynyl)pyridin-2-amine (2.22 g,47%) as a yellow solid: LC/MS (Table 1, Method c) R_(t)=1.62 min; MS m/z268 (M−H)⁻.

Step C: 4-chloro-3-ethynyl-5-nitropyridin-2-amine

To a solution of4-chloro-5-nitro-3-((trimethylsilyl)ethynyl)pyridin-2-amine (1.98 g,7.34 mmol) in DMF (25 mL) was added potassium fluoride on alumina (40 wt%, 2.67 g, 18.35 mmol). The suspension was stirred at ambienttemperature for about 1 h. Activated charcoal (0.3 g) was added and thesuspension was filtered though Celite®, washing with DMF (150 mL). Thesolvent was removed under reduced pressure and the crude material waspurified by silica gel chromatography eluting with a gradient of 0-10%MeOH in DCM to afford 4-chloro-3-ethynyl-5-nitropyridin-2-amine (1.03 g,71%) as a yellow solid: LC/MS (Table 1, Method n) R_(t)=0.59 min; MSm/z: 196 (M−H)⁻.

Step D: 4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine

To a solution of 4-chloro-3-ethynyl-5-nitropyridin-2-amine (0.16 g, 0.81mmol) in DMF (3 mL) was added chloro(1,5-cyclooctadiene)rhodium (I)dimer (0.02 g, 0.04 mmol) and tris(4-fluorophenyl)phosphine (0.128 g,0.405 mmol). The reaction mixture was degassed by bubbling argon for 15min. The reaction mixture was heated at about 80° C. for about 45 min.The solvent was removed under reduced pressure and the residue wassuspended in ether (10 mL). The precipitate was collected by filtrationand dried to give 4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (0.132 g,83%, contains approximately 6% mol of DMF and approximately 3% mol oftris(4-fluorophenyl)phosphine) as a brown solid: LC/MS (Table 1, Methoda) R_(t)=2.05 min; MS m/z 198 (M+H)⁺.

Step E:N-((1S,3R,4S)-3-ethyl-4-isocyanatocyclopentyl)cyclopropanesulfonamide

To a mixture of(1S,2R,4S)-4-(cyclopropanesulfonamido)-2-ethylcyclopentanecarboxylicacid (Preparation #Z.1, 1.00 g, 3.83 mmol) in t-BuOH (19.1 mL) was addedDPPA (0.826 mL, 3.83 mmol) and TEA (1.17 mL, 8.42 mmol). The reactionmixture was heated at about 70° C. for about 45 min. The reactionmixture was cooled to ambient temperature and concd under reducedpressure. The crude material was purified by silica gel chromatographyeluting with a gradient of 0-10% MeOH in DCM. The material was driedunder reduced pressure to giveN-((1S,3R,4S)-3-ethyl-4-isocyanatocyclopentyl)cyclopropanesulfonamidewith 30 mol % of t-BuOH as an excipient (0.97 g, 98%) as a colorlessoil: LC/MS (Table 1, Method n) R_(t)=0.56 min; MS m/z 259 (M+H)⁺.

Step F: N-((1S,3S,4R)-3-amino-4-ethylcyclopentyl)cyclopropanesulfonamidehydrochloride

A mixture ofN-((1S,3R,4S)-3-ethyl-4-isocyanatocyclopentyl)cyclopropanesulfonamide(0.972 g, 3.76 mmol) and aqueous HCl (6 N, 31.4 mL, 188 mmol) was heatedat about 100° C. for about 60 h. Aqueous HCl (12 N, 5 mL) was added andthe reaction mixture was heated at about 100° C. for about 18 h. Thereaction mixture was cooled to ambient temperature and concd underreduced pressure. The residue was treated with Et₂O (10 mL) and EtOAc(10 mL). The mixture was concd under reduced pressure. Water (5 mL) wasadded and the sample was lyophilized to giveN-((1S,3S,4R)-3-amino-4-ethylcyclopentyl)cyclopropane-sulfonamidehydrochloride (0.859 g, 85%) as a white solid: LC/MS (Table 1, Method a)R_(t)=1.28 min; MS m/z 233 (M+H)⁺.

Step G:N-((1S,3R,4S)-3-ethyl-4-(5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)cyclopentyl)cyclopropanesulfonamide

To a mixture of 4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (0.158 g,0.800 mmol) in DMF (8.7 mL) was added DIEA (0.419 mL, 2.399 mmol) andN-((1S,3S,4R)-3-amino-4-ethylcyclopentyl)cyclopropanesulfonamidehydrochloride (0.215 g, 0.800 mmol). The reaction mixture was heated atabout 60° C. for about 60 h. The temperature was increased to about 70°C. for about 2 h then DIEA (0.279 mL, 1.599 mmol) andN-((1S,3S,4R)-3-amino-4-ethylcyclopentyl)cyclopropanesulfonamidehydrochloride (0.093 g, 0.346 mmol) were added. The reaction mixture washeated at about 70° C. for about 2 h. AdditionalN-((1S,3S,4R)-3-amino-4-ethylcyclopentyl)cyclopropanesulfonamidehydrochloride (0.060 g, 0.223 mmol) was added and the reaction mixturewas heated at about 70° C. for about 30 min. Additional DIEA (0.279 mL,1.599 mmol) was added and the reaction mixture was heated at about 70°C. for about 1 h. The reaction mixture was cooled to ambient temperatureand concd in vacuo. The residue was dissolved in EtOAc (25 mL) andwashed with water (20 mL). The organic layer was separated, dried overanhydrous MgSO₄, filtered, and concd under reduced pressure. The crudematerial was purified by silica gel chromatography eluting with agradient of 0-5% MeOH in DCM to giveN-((1S,3R,4S)-3-ethyl-4-(5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)cyclopentyl)cyclopropanesulfonamide(0.134 g, 41%) as an orange solid: LC/MS (Table 1, Method n) R_(t)=0.66min; MS m/z 394 (M+H)⁺.

Step H:N-((1S,3R,4S)-3-ethyl-4-(5-nitro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)cyclopentyl)cyclopropanesulfonamide

To a solution ofN-((1S,3R,4S)-3-ethyl-4-(5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)cyclopentyl)cyclopropanesulfonamide(0.123 g, 0.314 mmol) in DMF (3.0 mL) at about 0° C. was added NaH (60%in mineral oil, 0.015 g, 0.37 mmol). The reaction mixture was stirredfor about 5 min. 4-Methylbenzene-1-sulfonyl chloride (0.060 g, 0.314mmol) was added and the reaction mixture was stirred for about 30 min.Additional NaH (60% in mineral oil, 0.007 g, 0.18 mmol) was added andthe reaction mixture was stirred for about 10 min. Additional NaH (60%in mineral oil, 0.005 g, 0.12 mmol) was added and the reaction mixturewas stirred for about 15 min. Additional 4-methylbenzene-1-sulfonylchloride (0.012 g, 0.063 mmol) was added and the reaction mixture wasstirred for about 40 min. The reaction mixture was concd under reducedpressure. The residue was dissolved in EtOAc (25 mL) and washed withwater (15 mL). The organic layer was separated, dried over anhydrousMgSO₄, filtered and concd under reduced pressure to giveN-((1S,3R,4S)-3-ethyl-4-(5-nitro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)cyclopentyl)-cyclopropanesulfonamide(0.218 g) as a red-orange oil containing 40 mol % DMF and 1 equivalentEtOAc: LC/MS (Table 1, Method n) R_(t)=0.88 min; MS m/z 548 (M+H)⁺.

Step I:N-((1S,3S,4R)-3-(5-amino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-4-ethylcyclopentyl)cyclopropanesulfonamide

To a suspension ofN-((1S,3R,4S)-3-ethyl-4-(5-nitro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)cyclopentyl)cyclopropanesulfonamide(0.172 g, 0.314 mmol) in EtOH (6 mL) was added tin (II) chloridedihydrate (0.142 g, 0.628 mmol). The reaction mixture was heated atabout 75° C. for about 15 h. Tin (II) chloride dihydrate (0.128 g, 0.565mmol) was added and the reaction mixture was heated at about 70° C. forabout 40 min then heated at about 80° C. for about 3 h. The reaction wascooled to ambient temperature and the solvent was removed under reducedpressure. The reaction mixture was diluted with EtOAc (20 mL) and washedwith 1N aqueous NaOH (10 mL), water (10 mL) and brine (10 mL). Theorganic layer was separated, dried over anhydrous MgSO₄, filtered andconcd under reduced pressure. EtOH (10 mL) was added and the mixture wasconcd under reduced pressure to giveN-((1S,3S,4R)-3-(5-amino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-4-ethylcyclopentyl)cyclopropanesulfonamide(0.160 g, 98%) as a yellow oil: LC/MS (Table 1, Method n) R_(t)=0.75min; MS m/z 518 (M+H)⁺.

Step J:N-((1S,3R,4S)-3-ethyl-4-(6-tosylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclopentyl)cyclopropanesulfonamide

A mixture ofN-((1S,3S,4R)-3-(5-amino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-4-ethylcyclopentyl)cyclopropanesulfonamide(0.160 g, 0.309 mmol), trimethyl orthoformate (3.42 mL, 30.9 mmol) andtoluene-4-sulfonic acid hydrate (0.006 g, 0.031 mmol) in MeOH (3.1 mL)was heated at about 65° C. for about 1 h then heated at about 60° C. forabout 14 h. The reaction mixture was cooled to ambient temperature andconcd under reduced pressure. The residue was dissolved in EtOAc (10 mL)and washed with saturated aqueous NaHCO₃ (5 mL), water (5 mL), and brine(5 mL). The organic layer was separated, dried over anhydrous MgSO₄,filtered and concd under reduced pressure to giveN-((1S,3R,4S)-3-ethyl-4-(6-tosylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclopentyl)cyclopropanesulfonamideas a yellow solid (0.130 g, 76%): LC/MS (Table 1, Method n) R_(t)=0.76min; MS m/z 528 (M+H)⁺.

Step K:N-((1S,3R,4S)-3-ethyl-4-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclopentyl)cyclopropanesulfonamide

A mixture ofN-((1S,3R,4S)-3-ethyl-4-(6-tosylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclopentyl)cyclopropanesulfonamide(0.119 g, 0.214 mmol) and 1N aqueous NaOH (0.428 mL, 0.428 mmol) in1,4-dioxane (2 mL) was heated at about 80° C. for about 40 min. AqueousNaOH (1 N, 0.428 mL, 0.428 mmol) was added and the reaction mixture washeated at about 80° C. for about for 3.5 h. The reaction mixture wascooled to ambient temperature and concd under reduced pressure. Theresidue was dissolved in EtOAc (10 mL) and water (10 mL). The pH wasadjusted to about 5 by the addition of 1 N aqueous HCl. The organiclayer was separated, dried over anhydrous MgSO₄, filtered and concdunder reduced pressure. The residue was triturated with Et₂O (5 mL) andthe solvent was removed by pippette. The residue was dried under reducedpressure to give a bright yellow solid that was purified by chiralchromatography [Table 2, Method 39, R_(t)=16.6 min, or =negative) togiveN-((1S,3R,4S)-3-ethyl-4-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclopentyl)cyclopropanesulfonamide(0.036 g, 45%): LC/MS (Table 1, Method a) R_(t)=1.71 min; MS m/z 374(M+H)⁺.

Example #24N-((1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentyl)cyclopropanesulfonamide

Step A: 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine

To a solution of 3,5-dibromopyrazin-2-amine (125 g, 494 mmol), TEA(207.0 mL, 1483 mmol), and copper (I) iodide (0.941 g, 4.94 mmol) in THF(1255 mL) was added PdCl₂(PPh₃)₂ (3.47 g, 4.94 mmol). The reactionmixture was cooled at about −5-0° C. and a solution of(trimethylsilyl)acetylene (65.0 mL, 470 mmol) in THF (157 mL) was addeddropwise over about 15 min. The reaction mixture was stirred at about−5-0° C. for about 1.5 h and then allowed to warm to rt overnight. Thereaction mixture was then filtered through a Celite® pad and washed withTHF until no further product eluted. The filtrate was concd underreduced pressure to give a brown-orange solid. The solid was trituratedand sonicated with warm petroleum ether (b.p. 30-60° C., 400 mL), cooledto rt, collected, washed with petroleum ether (b.p. 30-60° C.; 2×60 mL),and dried to give 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine(124 g, 93%, 93% purity) as a brown solid: LC/MS (Table 1, Method b)R_(t)=2.51 min; MS m/z: 270, 272 (M+H)⁺.

Step B: 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine

To a solution of 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine(3.00 g, 11.1 mmol) in DMF (60 mL) at about 0° C. was added NaH (60%dispersion in mineral oil, 0.577 g, 14 4 mmol) in three portions. Afterabout 15 min, p-toluenesulfonyl chloride (2.75 g, 14 4 mmol) was addedand the reaction was allowed to warm slowly to ambient temperature.After about 16 h, the reaction mixture was poured onto ice-cold water(120 mL) and the precipitate was collected by vacuum filtration. Thecrude solid was dissolved in DCM (15 mL) and purified by silica gelchromatography eluting with 100% DCM to give2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (2.16 g, 52%): LC/MS (Table 1,Method c) R_(t)=1.58 min; MS m/z: 352, 354 (M+H)⁺.

Step C: methyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylate

CO was bubbled into an orange solution of2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (50.0 g, 142 mmol) in DMF(2.50 L) within a 5 L round bottom flask for about 2 min.Bis(triphenylphosphine)-palladium(II) dichloride (9.96 g, 14 2 mmol),TEA (59 mL, 423 mmol) and MeOH (173.0 mL, 4259 mmol) were added and theflask was fitted with a balloon of CO. The mixture was heated at about95° C. under an atmosphere of CO (1 atmosphere). After stirringovernight, the reaction mixture was cooled to ambient temperatureovernight and poured into ice water (3.2 L). The mixture was stirred forabout 10 min and the precipitate was collected by filtration, whilewashing with water, and dried for 1 h. The crude material was dissolvedin DCM, separated from residual water, dried over anhydrous MgSO₄,filtered, added silica gel, and concd under reduced pressure to preparefor chromatography. The crude material was purified by silica gel columnchromatography eluting with 0-5% MeOH in DCM to yield methyl5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylate with 5 mol % DCM as anexcipient (40.7 g, 86%, 93% purity): LC/MS (Table 1, Method a)R_(t)=2.35 min; MS m/z 332 (M+H)⁺.

Step D: 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylic acid

HCl (6 N aqueous, 714 mL) was added to a yellow solution of methyl5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylate (17.8 g, 53 6 mmol) in1,4-dioxane (715 mL) within a 2 L round bottom flask, and the mixturewas heated at about 60° C. for about 16 h. The reaction mixture wascooled to ambient temperature. The organic solvent was removed underreduced pressure and the precipitate was collected, washed with water,and dried to yield 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylic acid(14.4 g, 85%) as a yellow solid: LC/MS (Table 1, Method a) R_(t)=1.63min; MS m/z 316 (M−H)⁻.

Step E: tert-butyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate

In a 500 mL round bottom flask,5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylic acid (14.4 g, 45.3 mmol),DPPA (9.78 mL, 45.3 mmol) and TEA (13.9 mL, 100 mmol) in t-BuOH (200 mL)were added to give an orange suspension. The mixture was heated at about70° C. for about 16 h, cooled to ambient temperature and the insolublematerial was filtered. The solvent was removed under reduced pressureand the crude material was purified by silica gel column chromatographyeluting with 25-60% EtOAc in heptane over 30 min to yield tert-butyl5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (9.75 g, 54%) as anoff-white solid: LC/MS (Table 1, Method a) R_(t)=2.79 min; MS m/z 389(M+H)⁺.

Step F: sodium4-(ethoxycarbonyl)-2-(methoxycarbonyl)-3-methylcyclopenta-1,3-dienolate

In a 12 L round bottom flask, NaH (60% dispersion in mineral oil, 159 g,3985 mmol) was added in portions to stirred anhydrous THF (4004 mL) togive a gray suspension. The mixture was cooled to about 5° C. in anice/salt bath before ethyl acetoacetate (506 mL, 3985 mmol, Alfa Aesar)in anhydrous THF (200 mL) was added dropwise via an addition funnel overabout 1 h during which time the temperature gradually increased to about18° C. After the addition was complete, the reaction was stirred atambient temperature for about 1 h and then a solution of methyl4-chloroacetoacetate (230 mL, 1993 mmol, Oakwood) in anhydrous THF (200mL) was added dropwise via an addition funnel over about 1 h. Theresulting mixture was stirred at ambient temperature for about 2 h andthen heated at about 50° C. for about 16 h. The reaction mixture wasconcd in vacuo. The orange solid was cooled to about 5° C. and anice/water mixture (2 L) was added. The suspension was mixed by rotatingon the rotovap without vacuum for about 30 min. The solid was collectedby filtration and washed with ice-cold water (750 mL). Once most of thesolvent (about 90%) had been removed, the wet solid was triturated withMeCN (750 mL), stirred for about 30 min and then the solid was collectedby filtration while washing with Et₂O (2×500 mL). The solid was dried inair for about 16 h and then in vacuo at about 55° C. to give sodium4-(ethoxycarbonyl)-2-(methoxycarbonyl)-3-methylcyclopenta-1,3-dienolate(485 g, 98%): ¹H NMR (DMSO-d₆) δ 3.95 (q, J=7.1 Hz, 2H), 3.48 (s, 3H),2.69 (q, J=2.0 Hz, 2H), 2.47 (t, J=2.1 Hz, 3H), 1.15 (t, J=7.1 Hz, 3H).

Step G: ethyl 2-methyl-4-oxocyclopent-2-enecarboxylate

In a 5 L round bottom flask, sodium4-(ethoxycarbonyl)-2-(methoxycarbonyl)-3-methylcyclopenta-1,3-dienolate(485 g, 1954 mmol), KCl (204 g, 2736 mmol, JT Baker), and AcOH (392 mL,6839 mmol, JT Baker) in toluene (1200 mL) and water (1200 mL) wereheated at reflux for about 6 h. The reaction mixture was allowed to coolto ambient temperature for about 16 h. The reaction mixture was thenpoured into a 12 L flask and diluted with water (3 L). Solid NaHCO₃ (450g, 5.3 mol) was added cautiously portionwise with stirring over about 1h. After about an additional 30 min of stirring, the basic aqueous phasewas separated and further extracted with Et₂O (4×400 mL). The combinedorganic layers were washed with water (4×500 mL) and brine (500 mL),dried over anhydrous MgSO₄, filtered, and concd under reduced pressureto yield a yellow oil that was purified by vacuum distillation (92-94°C., 0 4 mmHg) to give ethyl 2-methyl-4-oxocyclopent-2-enecarboxylate(229 g, 69%) as a yellow oil: ¹H NMR (CDCl₃) δ 6.04-6.01 (m, 1H),4.26-4.17 (m, 2H), 3.67 (m, 1H), 2.72 (m, 1H), 2.62 (m, 1H), 2.16 (s,3H), 1.32-1.27 (t, J=7.1 Hz, 3H).

Step H: ethyl 2-methyl-4-oxocyclopentanecarboxylate

In a 1 L round bottom flask jacketed flask, copper(I) chloride (0.736 g,7.43 mmol), (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (4.63 g,7.43 mmol), and sodium tert-butoxide (0.714 g, 7.43 mmol) in toluene(250 mL) were added to give a yellow solution. The mixture was stirredat ambient temperature for about 15 min. after which the solution becamebrown. The solution was cooled to about 5° C. andpolymethylhydrosiloxane (14.86 mL, 223 mmol) was added and the solutionwas stirred at about 5° C. for about 40 min. The solution was cooled toabout −15° C. and a solution of ethyl2-methyl-4-oxocyclopent-2-enecarboxylate (25.00 g, 149 mmol) andtert-butyl alcohol (61.7 mL, 654 mmol) in toluene (250 mL) was added inone portion. The reaction was stirred at −15° C. for 144 h. The reactionmixture was quenched by the addition of 1:1 ethanol/toluene (350 mL) andCelite® 545 (25 g). The mixture was stirred and allowed to warm toambient temperature. The reaction mixture was concd in vacuo, chasingwith heptane. Heptane (350 mL) was added to the residue and solids wereremoved by filtration. The filtrate was concd in vacuo and the crudeproduct was purified by silica gel chromatography using a gradient of 10to 50% EtOAc in heptane over 7 column volumes to give ethyl2-methyl-4-oxocyclopentanecarboxylate (scalemic mixture ofdiastereomers), predominantly (1S,2R)-ethyl2-methyl-4-oxocyclopentanecarboxylate (11.2 g, 42% yield) as a colorlessoil. ¹H NMR (400 MHz, CDCl₃) δ 4.19 (qd, J=7.1, 0.6, 2H), 3.17 (ddd,J=8.1, 6.8, 5.6, 1H), 2.76-2.56 (m, 2H), 2.67-2.46 (m, 2H), 2.43-2.29(m, 2H), 2.16 (ddd, J=18.3, 7.8, 1.7, 1H), 1.29 (t, J=7.2, 3H), 1.06 (d,J=7.0, 3H).

Step I: ethyl 4-(dibenzylamino)-2-methylcyclopentanecarboxylate

A round bottom flask was charged with ethyl2-methyl-4-oxocyclopentanecarboxylate (10.0 g, 58.8 mmol) and DCE (180mL). The solution was cooled to about 0° C. and AcOH (5.7 mL, 100 mmol)and dibenzylamine (11.3 mL, 58 8 mmol) were added dropwise, resulting information of a thick suspension. The reaction mixture was warmed toabout 10° C. and sodium triacetoxyborohydride (21.2 g, 100 mmol) wasadded portionwise. The reaction mixture was stirred at ambienttemperature for about 20 h then slowly poured into stirred saturatedaqueous NaHCO₃ (300 mL) and stirred for about 20 min. The layers wereseparated and the aqueous phase was extracted with DCM (3×100 mL). Thecombined organic extracts were washed with brine (2×100 mL), dried overanhydrous Na₂SO₄, and concd under reduced pressure. The crude yellow oilwas purified via silica gel chromatography eluting with a gradient of0-30% EtOAc in heptane to give ethyl4-(dibenzylamino)-2-methylcyclopentanecarboxylate (scalemic mixture ofdiastereomer), predominantly (1S,2R,4S)-ethyl4-(dibenzylamino)-2-methylcyclopentanecarboxylate) (15.5 g, 75%) as acolorless oil: ¹H NMR (pyridine-d₅) δ 7.53 (dd, J=0.9, 7.9 Hz, 4H),7.43-7.35 (m, 4H), 7.33-7.25 (m, 2H), 4.22-4.06 (m, 2H), 3.79 (d, J=14.2Hz, 2H), 3.70 (d, J=14.2 Hz, 2H), 3.34-3.22 (m, 1H), 2.76 (dd, J=7.9,16.6 Hz, 1H), 2.25-2.13 (m, 1H), 2.09-1.94 (m, 2H), 1.88-1.79 (m, 1H),1.52 (dd, J=10.5, 22.5 Hz, 1H), 1.16 (t, J=7.1 Hz, 3H), 0.98 (d, J=7.0Hz, 3H).

Step J: 4-(dibenzylamino)-2-methylcyclopentanecarboxylic acid

Ethyl 4-(dibenzylamino)-2-methylcyclopentanecarboxylate (3.65 g, 10.38mmol) was dissolved in a mixture of HCl (6 N aqueous, 20 mL) and1,4-dioxane (50 mL) and the resulting mixture was heated at about 60° C.for about 72 h. The organic solvent was removed under reduced pressure.The aqueous phase was neutralized by the addition of saturated aqueousNaHCO₃ (40 mL) and extracted with EtOAc (50 mL). The organic layer waswashed with brine (40 mL), dried over anhydrous MgSO₄ and concd underreduced pressure to yield4-(dibenzylamino)-2-methylcyclopentanecarboxylic acid (3.3 g, 98%) as awhite amorphous solid: LC/MS (Table 1, Method a) R_(t)=1.66 min; MS m/z324 (M+H)⁺.

Step K: 2-bromo-1-(4-(dibenzylamino)-2-methylcyclopentyl)ethanone

Oxalyl chloride (4.37 mL, 49.9 mmol) was slowly added to a solution of4-(dibenzylamino)-2-methylcyclopentanecarboxylic acid (7.34 g, 22.7mmol) in DCM (100 mL), (note: mild gas evolution) followed by a dropwiseaddition of DMF (0.26 mL, 3.41 mmol). The mixture was stirred at ambienttemperature for about 14 h. The solvent was removed under reducedpressure to yield a beige amorphous solid, which was dissolved in THFand MeCN (1:1, 100 mL). The resulting solution was added to a solutionof trimethylsilyldiazomethane (2 M in Et₂O, 39.7 mL, 79 mmol) in THF andMeCN (1:1, 100 mL) at about 0° C. The resulting mixture was stirred atabout 0° C. for about 3 h and then was quenched by a dropwise additionof HBr (48% aqueous, 25 mL, 221 mmol). The resulting mixture wasneutralized by a dropwise addition of saturated aqueous NaHCO₃ (300 mL)and the layers were separated. The organic layer was dried overanhydrous MgSO₄ and concd under reduced pressure. The residue waspurified by silica gel chromatography eluting with 5% to 45% of EtOAc inheptane to yield2-bromo-1-(4-(dibenzylamino)-2-methylcyclopentyl)ethanone (6.3 g, 69%)as a yellow oil: LC/MS (Table 1, Method a) R_(t)=2.90 min; MS m/z 400,402 (M+H)⁺.

Step L: tert-butyl2-(4-(dibenzylamino)-2-methylcyclopentyl)-2-oxoethyl(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)carbamate

A solution of tert-butyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate(0.59 g, 1.519 mmol, Example #3 Step E) in DMF (5 mL) was added dropwiseto a suspension of NaH (60% dispersion in mineral oil, 0.058 g, 1.45mmol) in DMF (5 mL), at about 0° C. The resulting mixture was stirred atabout 0° C. for about 30 min and then added dropwise to a solution of2-bromo-1-(4-(dibenzylamino)-2-methylcyclopentyl)ethanone (0.73 g, 1.8mmol) in DMF (10 mL) at about 0° C. The resulting mixture was stirred atabout 0° C. for about 1 h and the solvent was removed under reducedpressure. The residue was partitioned between saturated aqueous NaHCO₃and EtOAc (100 mL each). The organic phase was separated, dried overanhydrous MgSO₄ and concd under reduced pressure to yield tert-butyl2-(4-(dibenzylamino)-2-methylcyclopentyl)-2-oxoethyl(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)carbamate(1.04 g, 97%) as a yellow amorphous solid: LC/MS (Table 1, Method a)R_(t)=3.30 min; MS m/z 708 (M+H)⁺.

Step M:1-(4-(dibenzylamino)-2-methylcyclopentyl)-2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)ethanone

tert-Butyl2-(4-(dibenzylamino)-2-methylcyclopentyl)-2-oxoethyl(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)carbamate(6.19 g, 8.75 mmol) was dissolved in HCl (4 N in 1,4-dioxane, 25 mL).The reaction mixture was stirred at ambient temperature for about 2 h.The solvent was removed under reduced pressure and the residue waspartitioned between saturated aqueous NaHCO₃ and EtOAc (100 mL each).The organic phase was washed with brine (80 mL), dried over anhydrousMgSO₄ and concd under reduced pressure to yield1-(4-(dibenzylamino)-2-methylcyclopentyl)-2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)ethanone(5.2 g, 98%) as a brown amorphous solid: LC/MS (Table 1, Method a)R_(t)=3.00 min; MS m/z 608 (M+H)⁺.

Step N:N,N-dibenzyl-3-methyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentanamine

A mixture of1-(4-(dibenzylamino)-2-methylcyclopentyl)-2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)ethanone(5.32 g, 8.75 mmol) and Lawesson's reagent (1.88 g, 4.64 mmol) washeated at about 60° C. for about 2 h. Lawesson's reagent (1.88 g, 4.64mmol) was added. The reaction mixture was stirred at about 60° C. forabout 1 h. The solvent was removed under reduced pressure and theresidue was purified by silica gel chromatography eluting with agradient of 0-8% MeOH in DCM to yieldN,N-dibenzyl-3-methyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentanamine(4.47 g, 87%) as a brown amorphous solid: LC/MS (Table 1, Method a)R_(t)=2.99 min; MS m/z 590 (M+H)⁺.

Step O:N,N-dibenzyl-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentanamine

N,N-Dibenzyl-3-methyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentan-amine(4.47 g, 7.58 mmol) was dissolved in 1,4-dioxane (40 mL). NaOH (2 Naqueous, 4 mL) was added and the reaction mixture was heated at about90° C. for about 80 min. The organic solvent was removed under reducedpressure and the residue was treated with saturated aqueous NH₄Cl (70mL) and extracted with DCM (2×60 mL). The combined organic extracts werewashed with brine (70 mL), dried over anhydrous MgSO₄ and concd underreduced pressure. The residue was purified by silica gel chromatographyeluting with a gradient of 0-8% MeOH in DCM to yieldN,N-dibenzyl-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentan-amine(1.84 g, 56%) as a yellow oil: LC/MS (Table 1, Method a) R_(t)=2.31 min;MS m/z 436 (M+H)⁺.

Step P:N,N-dibenzyl-3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentanamine

To the suspension of sodium hydride (60% dispersion in mineral oil,0.382 g, 9.55 mmol) in DMF (50 mL) was added drop-wise a solution ofN,N-dibenzyl-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentanamine(3.96 g, 9.09 mmol) in DMF (50 mL) at 0° C. The resulting solution wasstirred at ambient temperature for about 10 min. SEM chloride (1.774 mL,10.0 mmol) was added drop-wise and the solution was stirred for about 1h. The solvent was removed under reduced pressure and the residue waspartitioned between water and EtOAc (200 mL each). The organic layer waswashed with brine (100 mL), dried over anhydrous MgSO₄, filtered andconcd. The residue was purified by silica gel chromatography elutingwith 10-80% EtOAc in DCM to yieldN,N-dibenzyl-3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentanamine(3.1 g, 60% yield) as an off-white amorphous solid. LC/MS (Table 1,Method a) R_(t)=3.32 min; MS m/z 566 (M+H)⁺.

Step Q:3-Methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentanamine

To a solution ofN,N-dibenzyl-3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentanamine(3.0 g, 5.30 mmol) in trifluoroethanol (200 mL) was added 20% wetpalladium hydroxide on carbon (0.6 g, 4.27 mmol). The mixture wasstirred under 40 psi of hydrogen at about 50° C. for about 90 min. Thecatalyst was removed by filtration through a pad of Celite® and thefiltrate was concd under reduced pressure to yield3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentanamine(2.0 g, 98% yield) as a brown amorphous solid. LC/MS (Table 1, Method a)R_(t)=1.86 min; MS m/z 386 (M+H)⁺.

Step R:N-(3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentyl)cyclopropanesulfonamide

To a solution of3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentanamine(0.27 g, 0.7 mmol) and DIEA (0.18 mL, 1.05 mmol) in DCM (5 mL) was addedcyclopropanesulfonyl chloride (0.098 g, 0.7 mmol) drop-wise. Theresulting mixture was stirred at ambient temperature for about 1 h.Another 0.18 mL of DIEA and 0.098 g of cyclopropanesulfonyl chloridewere added and the reaction was continued for about 3 h. The solvent wasremoved and the residue was partitioned between saturated aqueousammonium chloride and EtOAc (20 mL each). The organic layer was washedwith brine (10 mL), dried over anhydrous MgSO₄, filtered and concd. Theresidue was purified by silica gel chromatography (100% DCM for 5 min,then to 6% MeOH in DCM over next 30 min) to yieldN-(3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentyl)cyclopropanesulfonamide(0.18 g, 52% yield) as an off-white solid. LC/MS (Table 1, Method a)R_(t)=2.45 min; MS m/z 490 (M+H)⁺.

Step S:N-((1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentyl)cyclopropanesulfonamide

To the solution of3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentyl)cyclopropanesulfonamide(0.18 g, 0.368 mmol) in DCM (2.5 mL) was added TFA (0.9 mL). Theresulting mixture was stirred at ambient temperature for about 2 h. Thesolvents were removed under reduced pressure and the residue dried underhigh vacuum. The residue was dissolved in 1,4-dioxane (3 mL) and 28%ammonium hydroxide solution in water (2.5 mL). The mixture was heated atabout 60° C. for about 2 h. The solvents were removed under reducedpressure and the residue was purified by using general procedure AA(Table 2, Method 32, R_(t)=20.9 min, or =negative) to yieldN-((1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentyl)cyclopropanesulfonamide(0.088 g, 66% yield) as a white solid. LC/MS (Table 1, Method a)R_(t)=1.52 min; MS m/z 360 (M+H)⁺.

Example #25N-((1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentyl)-3,3-difluoroazetidine-1-sulfonamide

Step A: 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine

To a solution of 3,5-dibromopyrazin-2-amine (125 g, 494 mmol), TEA(207.0 mL, 1483 mmol), and copper (I) iodide (0.941 g, 4.94 mmol) in THF(1255 mL) was added PdCl₂(PPh₃)₂ (3.47 g, 4.94 mmol). The reactionmixture was cooled at about −5-0° C. and a solution of(trimethylsilyl)acetylene (65.0 mL, 470 mmol) in THF (157 mL) was addeddropwise over about 15 min. The reaction mixture was stirred at about−5-0° C. for about 1.5 h and then allowed to warm to rt overnight. Thereaction mixture was then filtered through a Celite® pad and washed withTHF until no further product eluted. The filtrate was concd underreduced pressure to give a brown-orange solid. The solid was trituratedand sonicated with warm petroleum ether (b.p. 30-60° C., 400 mL), cooledto rt, collected, washed with petroleum ether (b.p. 30-60° C.; 2×60 mL),and dried to give 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine(124 g, 93%, 93% purity) as a brown solid: LC/MS (Table 1, Method b)R_(t)=2.51 min; MS m/z: 270, 272 (M+H)⁺.

Step B: 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine

To a solution of 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine(3.00 g, 11.1 mmol) in DMF (60 mL) at about 0° C. was added NaH (60%dispersion in mineral oil, 0.577 g, 14 4 mmol) in three portions. Afterabout 15 min, p-toluenesulfonyl chloride (2.75 g, 14 4 mmol) was addedand the reaction was allowed to warm slowly to ambient temperature.After about 16 h, the reaction mixture was poured onto ice-cold water(120 mL) and the precipitate was collected by vacuum filtration. Thecrude solid was dissolved in DCM (15 mL) and purified by silica gelchromatography eluting with DCM to give2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (2.16 g, 52%): LC/MS (Table 1,Method c) R_(t)=1.58 min; MS m/z: 352, 354 (M+H)⁺.

Step C: methyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylate

CO was bubbled into an orange solution of2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (50.0 g, 142 mmol) in DMF(2.50 L) within a 5 L round bottom flask for about 2 min.Bis(triphenylphosphine)-palladium(II) dichloride (9.96 g, 14 2 mmol),TEA (59 mL, 423 mmol) and MeOH (173.0 mL, 4259 mmol) were added and theflask was fitted with a balloon of CO. The mixture was heated at about95° C. under an atmosphere of CO (1 atmosphere). After stirringovernight, the reaction mixture was cooled to ambient temperatureovernight and poured into ice water (3.2 L). The mixture was stirred forabout 10 min and the precipitate was collected by filtration, whilewashing with water, and dried for 1 h. The crude material was dissolvedin DCM, separated from residual water, dried over anhydrous MgSO₄,filtered, added silica gel, and concd under reduced pressure to preparefor chromatography. The crude material was purified by silica gel columnchromatography eluting with 0-5% MeOH in DCM to yield methyl5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylate with 5 mol % DCM as anexcipient (40.7 g, 86%, 93% purity): LC/MS (Table 1, Method a)R_(t)=2.35 min; MS m/z 332 (M+H)⁺.

Step D: 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylic acid

HCl (6 N aqueous, 714 mL) was added to a yellow solution of methyl5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylate (17.8 g, 53 6 mmol) in1,4-dioxane (715 mL) within a 2 L round bottom flask, and the mixturewas heated at about 60° C. for about 16 h. The reaction mixture wascooled to ambient temperature. The organic solvent was removed underreduced pressure and the precipitate was collected, washed with water,and dried to yield 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylic acid(14.4 g, 85%) as a yellow solid: LC/MS (Table 1, Method a) R_(t)=1.63min; MS m/z 316 (M−H)⁻.

Step E: tert-butyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate

In a 500 mL round bottom flask,5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylic acid (14.4 g, 45.3 mmol),DPPA (9.78 mL, 45.3 mmol) and TEA (13.9 mL, 100 mmol) in t-BuOH (200 mL)were added to give an orange suspension. The mixture was heated at about70° C. for about 16 h, cooled to ambient temperature and the insolublematerial was filtered. The solvent was removed under reduced pressureand the crude material was purified by silica gel column chromatographyeluting with 25-60% EtOAc in heptane over 30 min to yield tert-butyl5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (9.75 g, 54%) as anoff-white solid: LC/MS (Table 1, Method a) R_(t)=2.79 min; MS m/z 389(M+H)⁺.

Step F: sodium4-(ethoxycarbonyl)-2-(methoxycarbonyl)-3-methylcyclopenta-1,3-dienolate

In a 12 L round bottom flask, NaH (60% dispersion in mineral oil, 159 g,3985 mmol) was added in portions to stirred anhydrous THF (4004 mL) togive a gray suspension. The mixture was cooled to about 5° C. in anice/salt bath before ethyl acetoacetate (506 mL, 3985 mmol, Alfa Aesar)in anhydrous THF (200 mL) was added dropwise via an addition funnel overabout 1 h during which time the temperature gradually increased to about18° C. After the addition was complete, the reaction was stirred atambient temperature for about 1 h and then a solution of methyl4-chloroacetoacetate (230 mL, 1993 mmol, Oakwood) in anhydrous THF (200mL) was added dropwise via an addition funnel over about 1 h. Theresulting mixture was stirred at ambient temperature for about 2 h andthen heated at about 50° C. for about 16 h. The reaction mixture wasconcd in vacuo. The orange solid was cooled to about 5° C. and anice/water mixture (2 L) was added. The suspension was mixed by rotatingon the rotovap without vacuum for about 30 min. The solid was collectedby filtration and washed with ice-cold water (750 mL). Once most of thesolvent (about 90%) had been removed, the wet solid was triturated withMeCN (750 mL), stirred for about 30 min and then the solid was collectedby filtration while washing with Et₂O (2×500 mL). The solid was dried inair for about 16 h and then in vacuo at about 55° C. to give sodium4-(ethoxycarbonyl)-2-(methoxycarbonyl)-3-methylcyclopenta-1,3-dienolate(485 g, 98%): ¹H NMR (DMSO-d₆) δ 3.95 (q, J=7.1 Hz, 2H), 3.48 (s, 3H),2.69 (q, J=2.0 Hz, 2H), 2.47 (t, J=2.1 Hz, 3H), 1.15 (t, J=7.1 Hz, 3H).

Step G: ethyl 2-methyl-4-oxocyclopent-2-enecarboxylate

In a 5 L round bottom flask, sodium4-(ethoxycarbonyl)-2-(methoxycarbonyl)-3-methylcyclopenta-1,3-dienolate(485 g, 1954 mmol), KCl (204 g, 2736 mmol, JT Baker), and AcOH (392 mL,6839 mmol, JT Baker) in toluene (1200 mL) and water (1200 mL) wereheated at reflux for about 6 h. The reaction mixture was allowed to coolto ambient temperature for about 16 h. The reaction mixture was thenpoured into a 12 L flask and diluted with water (3 L). Solid NaHCO₃ (450g, 5.3 mol) was added cautiously portionwise with stirring over about 1h. After about an additional 30 min of stirring, the basic aqueous phasewas separated and further extracted with Et₂O (4×400 mL). The combinedorganic layers were washed with water (4×500 mL) and brine (500 mL),dried over anhydrous MgSO₄, filtered, and concd under reduced pressureto yield a yellow oil that was purified by vacuum distillation (92-94°C., 0 4 mmHg) to give ethyl 2-methyl-4-oxocyclopent-2-enecarboxylate(229 g, 69%) as a yellow oil: ¹H NMR (CDCl₃) δ 6.04-6.01 (m, 1H),4.26-4.17 (m, 2H), 3.67 (m, 1H), 2.72 (m, 1H), 2.62 (m, 1H), 2.16 (s,3H), 1.32-1.27 (t, J=7.1 Hz, 3H).

Step H: ethyl 2-methyl-4-oxocyclopentanecarboxylate

In a 1 L round-bottomed flask jacketed flask, copper(I) chloride (0.736g, 7.43 mmol), (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (4.63g, 7.43 mmol), and sodium tert-butoxide (0.714 g, 7.43 mmol) in toluene(250 mL) were added to give a yellow solution. The mixture was stirredat ambient temperature for about 15 min. after which the solution becamebrown. The solution was cooled to about 5° C. andpolymethylhydrosiloxane (14.86 mL, 223 mmol) was added and the solutionwas stirred at about 5° C. for about 40 min. The solution was cooled toabout −15° C. and a solution of ethyl2-methyl-4-oxocyclopent-2-enecarboxylate (25.00 g, 149 mmol) andtert-butyl alcohol (61.7 mL, 654 mmol) in toluene (250 mL) was added inone portion. The reaction stirred at −15° C. for 144 h. The reactionmixture was quenched by the addition of 1:1 ethanol/toluene (350 mL) andCelite® 545 (25 g). The mixture was stirred and allowed to warm toambient temperature. The reaction mixture was concd in vacuo, chasingwith heptane. Heptane (350 mL) was added to the residue and solids wereremoved by filtration. The filtrate was concd in vacuo and the crudeproduct was purified by silica gel chromatography using a gradient of 10to 50% EtOAc in heptane over 7 column volumes to give ethyl2-methyl-4-oxocyclopentanecarboxylate (scalemic mixture ofdiastereomers), predominantly (1S,2R)-ethyl2-methyl-4-oxocyclopentanecarboxylate (11.2 g, 42% yield) as a colorlessoil. ¹H NMR (400 MHz, CDCl₃) δ 4.19 (qd, J=7.1, 0.6, 2H), 3.17 (ddd,J=8.1, 6.8, 5.6, 1H), 2.76-2.56 (m, 2H), 2.67-2.46 (m, 2H), 2.43-2.29(m, 2H), 2.16 (ddd, J=18.3, 7.8, 1.7, 1H), 1.29 (t, J=7.2, 3H), 1.06 (d,J=7.0, 3H).

Step I: ethyl 4-(dibenzylamino)-2-methylcyclopentanecarboxylate

A round bottom flask was charged with ethyl2-methyl-4-oxocyclopentanecarboxylate (10.0 g, 58.8 mmol) and DCE (180mL). The solution was cooled to about 0° C. and AcOH (5.7 mL, 100 mmol)and dibenzylamine (11.3 mL, 58 8 mmol) were added dropwise, resulting information of a thick suspension. The reaction mixture was warmed toabout 10° C. and sodium triacetoxyborohydride (21.2 g, 100 mmol) wasadded portionwise. The reaction mixture was stirred at ambienttemperature for about 20 h then slowly poured into stirred saturatedaqueous NaHCO₃ (300 mL) and stirred for about 20 min. The layers wereseparated and the aqueous phase was extracted with DCM (3×100 mL). Thecombined organic extracts were washed with brine (2×100 mL), dried overanhydrous Na₂SO₄, and concd under reduced pressure. The crude yellow oilwas purified via silica gel chromatography eluting with a gradient of0-30% EtOAc in heptane to give ethyl4-(dibenzylamino)-2-methylcyclopentanecarboxylate (scalemic mixture ofdiastereomers), predominantly (1S,2R,4S) ethyl4-(dibenzylamino)-2-methylcyclopentanecarboxylate (15.5 g, 75%) as acolorless oil: ¹H NMR (pyridine-d₅) δ 7.53 (dd, J=0.9, 7.9 Hz, 4H),7.43-7.35 (m, 4H), 7.33-7.25 (m, 2H), 4.22-4.06 (m, 2H), 3.79 (d, J=14.2Hz, 2H), 3.70 (d, J=14.2 Hz, 2H), 3.34-3.22 (m, 1H), 2.76 (dd, J=7.9,16.6 Hz, 1H), 2.25-2.13 (m, 1H), 2.09-1.94 (m, 2H), 1.88-1.79 (m, 1H),1.52 (dd, J=10.5, 22.5 Hz, 1H), 1.16 (t, J=7.1 Hz, 3H), 0.98 (d, J=7.0Hz, 3H).

Step J: 4-(dibenzylamino)-2-methylcyclopentanecarboxylic acid

Ethyl 4-(dibenzylamino)-2-methylcyclopentanecarboxylate (3.65 g, 10.38mmol) was dissolved in a mixture of HCl (6 N aqueous, 20 mL) and1,4-dioxane (50 mL) and the resulting mixture was heated at about 60° C.for about 72 h. The organic solvent was removed under reduced pressure.The aqueous phase was neutralized by the addition of saturated aqueousNaHCO₃ (40 mL) and extracted with EtOAc (50 mL). The organic layer waswashed with brine (40 mL), dried over anhydrous MgSO₄ and concd underreduced pressure to yield4-(dibenzylamino)-2-methylcyclopentanecarboxylic acid (3.3 g, 98%) as awhite amorphous solid: LC/MS (Table 1, Method a) R_(t)=1.66 min; MS m/z324 (M+H)⁺.

Step K: 2-bromo-1-(4-(dibenzylamino)-2-methylcyclopentyl)ethanone

Oxalyl chloride (4.37 mL, 49.9 mmol) was slowly added to a solution of4-(dibenzylamino)-2-methylcyclopentanecarboxylic acid (7.34 g, 22.7mmol) in DCM (100 mL), (note: mild gas evolution) followed by a dropwiseaddition of DMF (0.26 mL, 3.41 mmol). The mixture was stirred at ambienttemperature for about 14 h. The solvent was removed under reducedpressure to yield a beige amorphous solid, which was dissolved in THFand MeCN (1:1, 100 mL). The resulting solution was added to a solutionof trimethylsilyldiazomethane (2 M in Et₂O, 39.7 mL, 79 mmol) in THF andMeCN (1:1, 100 mL) at about 0° C. The resulting mixture was stirred atabout 0° C. for about 3 h and then was quenched by a dropwise additionof HBr (48% aqueous, 25 mL, 221 mmol). The resulting mixture wasneutralized by a dropwise addition of saturated aqueous NaHCO₃ (300 mL)and the layers were separated. The organic layer was dried overanhydrous MgSO₄ and concd under reduced pressure. The residue waspurified by silica gel chromatography eluting with 5% to 45% of EtOAc inheptane to yield2-bromo-1-(4-(dibenzylamino)-2-methylcyclopentyl)ethanone (6.3 g, 69%)as a yellow oil: LC/MS (Table 1, Method a) R_(t)=2.90 min; MS m/z 400,402 (M+H)⁺.

Step L: tert-butyl2-(4-(dibenzylamino)-2-methylcyclopentyl)-2-oxoethyl(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)carbamate

A solution of tert-butyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate(0.59 g, 1.519 mmol, Example #3 Step E) in DMF (5 mL) was added dropwiseto a suspension of NaH (60% dispersion in mineral oil, 0.058 g, 1.45mmol) in DMF (5 mL), at about 0° C. The resulting mixture was stirred atabout 0° C. for about 30 min and then added dropwise to a solution of2-bromo-1-(4-(dibenzylamino)-2-methylcyclopentyl)ethanone (0.73 g, 1.8mmol) in DMF (10 mL) at about 0° C. The resulting mixture was stirred atabout 0° C. for about 1 h and the solvent was removed under reducedpressure. The residue was partitioned between saturated aqueous NaHCO₃and EtOAc (100 mL each). The organic phase was separated, dried overanhydrous MgSO₄ and concd under reduced pressure to yield tert-butyl2-(4-(dibenzylamino)-2-methylcyclopentyl)-2-oxoethyl(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)carbamate(1.04 g, 97%) as a yellow amorphous solid: LC/MS (Table 1, Method a)R_(t)=3.30 min; MS m/z 708 (M+H)⁺.

Step M:1-(4-(dibenzylamino)-2-methylcyclopentyl)-2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)ethanone

tert-Butyl2-(4-(dibenzylamino)-2-methylcyclopentyl)-2-oxoethyl(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)carbamate(6.19 g, 8.75 mmol) was dissolved in HCl (4 N in 1,4-dioxane, 25 mL).The reaction mixture was stirred at ambient temperature for about 2 h.The solvent was removed under reduced pressure and the residue waspartitioned between saturated aqueous NaHCO₃ and EtOAc (100 mL each).The organic phase was washed with brine (80 mL), dried over anhydrousMgSO₄ and concd under reduced pressure to yield1-(4-(dibenzylamino)-2-methylcyclopentyl)-2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)ethanone(5.2 g, 98%) as a brown amorphous solid: LC/MS (Table 1, Method a)R_(t)=3.00 min; MS m/z 608 (M+H)⁺.

Step N:N,N-dibenzyl-3-methyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentanamine

A mixture of1-(4-(dibenzylamino)-2-methylcyclopentyl)-2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)ethanone(5.32 g, 8.75 mmol) and Lawesson's reagent (1.88 g, 4.64 mmol) washeated at about 60° C. for about 2 h. Additional Lawesson's reagent(1.88 g, 4.64 mmol) was added. The reaction mixture was stirred at about60° C. for about 1 h. The solvent was removed under reduced pressure andthe residue was purified by silica gel chromatography eluting with agradient of 0-8% MeOH in DCM to yieldN,N-dibenzyl-3-methyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentanamine(4.47 g, 87%) as a brown amorphous solid: LC/MS (Table 1, Method a)R_(t)=2.99 min; MS m/z 590 (M+H)⁺.

Step O:N,N-dibenzyl-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentanamine

N,N-Dibenzyl-3-methyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentan-amine(4.47 g, 7.58 mmol) was dissolved in 1,4-dioxane (40 mL). NaOH (2 Naqueous, 4 mL) was added and the reaction mixture was heated at about90° C. for about 80 min. The organic solvent was removed under reducedpressure and the residue was treated with saturated aqueous NH₄Cl (70mL) and extracted with DCM (2×60 mL). The combined organic extracts werewashed with brine (70 mL), dried over anhydrous MgSO₄ and concd underreduced pressure. The residue was purified by silica gel chromatographyeluting with a gradient of 0-8% MeOH in DCM to yieldN,N-dibenzyl-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentan-amine(1.84 g, 56%) as a yellow oil: LC/MS (Table 1, Method a) R_(t)=2.31 min;MS m/z 436 (M+H)⁺.

Step P:N,N-dibenzyl-3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentanamine

To the suspension of sodium hydride (60% dispersion in mineral oil,0.382 g, 9.55 mmol) in DMF (50 mL) was added a solution ofN,N-dibenzyl-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentanamine(3.96 g, 9.09 mmol) in DMF (50 mL) drop-wise at about 0° C. Theresulting solution was stirred at ambient temperature for about 10 min.SEM chloride (1.774 mL, 10.0 mmol) was added drop-wise and the solutionwas stirred for about 1 h. The solvent was removed under reducedpressure and the residue was partitioned between water and EtOAc (200 mLeach). The organic layer was washed with brine (100 mL), dried overanhydrous MgSO₄, filtered and concd. The residue was purified by silicagel column chromatography eluting with 10-80% EtOAc in DCM to yieldN,N-dibenzyl-3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentanamine(3.1 g, 60% yield) as an off-white amorphous solid. LC/MS (Table 1,Method a) R_(t)=3.32 min; MS m/z 566 (M+H)⁺.

Step Q:3-Methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentanamine

To a solution ofN,N-dibenzyl-3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentanamine(3.0 g, 5.30 mmol) in trifluoroethanol (200 mL) was added 20% wetpalladium hydroxide on carbon (0.6 g, 4.27 mmol). The mixture wasstirred under 40 psi of hydrogen at about 50° C. for about 90 min. Thecatalyst was removed by filtration through a pad of Celite® and thefiltrate was concd under reduced pressure to yield3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentanamine(2.0 g, 98% yield) as a brown amorphous solid. LC/MS (Table 1, Method a)R_(t)=1.86 min; MS m/z 386 (M+H)⁺.

Step R:N-3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentyl)-2-oxooxazolidine-3-sulfonamide

To a solution of3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentanamine(0.50 g, 1.3 mmol) and 2-chloroethyl chlorosulfonylcarbamate (0.288 g,1.297 mmol, prepared as detailed in Biorg. Med. Chem. Lett, 2006 16,3367-3370) in DCM (16 mL) was added TEA (0.542 mL, 3.89 mmol) drop-wise.The mixture was stirred at ambient temperature for about 2 h. Thesolvent was removed under reduced pressure and the residue waspartitioned between water and EtOAc (30 mL each). The organic layer waswashed with brine (20 mL), dried over anhydrous MgSO₄, filtered andconcd under reduced pressure. The residue was purified by silica gelchromatography (0% DCM for 5 min, then to 6% MeOH in DCM over the next30 min.) to yieldN-3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentyl)-2-oxooxazolidine-3-sulfonamide(0.24 g, 35% yield) as an off-white solid. LC/MS (Table 1, Method a)R_(t)=2.42 min; MS m/z 535 (M+H)⁺.

Step S:3,3-difluoro-N-3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentyl)azetidine-1-sulfonamide

To a solution of3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentyl)-2-oxooxazolidine-3-sulfonamide(0.24 g, 0.449 mmol) in MeCN (1.5 mL) was added (3,3-difluoroazetidinehydrochloride (0.07 g, 0.539 mmol, Matirx Scientific) and DIEA (0.196mL, 1.122 mmol). The mixture was heated in the microwave at about 120°C. for about 30 min. The solvent was removed under reduced pressure andthe residue was partitioned between saturated solution of ammoniumchloride in water and EtOAc (20 mL each). The organic layer was washedwith brine (10 mL), dried over anhydrous MgSO₄, filtered and concd toyield3,3-difluoro-N-3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentyl)azetidine-1-sulfonamide(0.2 g, 82% yield) as an off-white amorphous solid. LC/MS (Table 1,Method a) R_(t)=2.61 min; MS m/z 541 (M+H)⁺.

Step T:N-((1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentyl)-3,3-difluoroazetidine-1-sulfonamide

To a solution of3,3-difluoro-N-3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentyl)azetidine-1-sulfonamide(0.20 g, 0.370 mmol) in DCM (2.5 mL) was added TFA (0.9 mL). Theresulting mixture was stirred at ambient temperature for about 2 h. Thesolvents were removed under reduced pressure and the residue was driedunder high vacuum. The residue was dissolved in 1,4-dioxane (3 mL) and28% ammonium hydroxide solution in water (2.5 mL) and the mixture washeated at about 60° C. for about 2 h. The solvents were removed underreduced pressure and the residue was purified by using general procedureAA (Table 2, Method 32, R_(t)=15.3 min, or =negative) to yieldN-((1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentyl)-3,3-difluoroazetidine-1-sulfonamide(0.077 g, 51%) as a yellow solid. LC/MS (Table 1, Method a) R_(t)=1.75min; MS m/z 411 (M+H)⁺.

Example #26*5-((3S,5R)-5-ethyl-1-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrrolidin-3-ylamino)pyrazine-2-carbonitrileoxalate

To slurry of palladium hydroxide on carbon (20 mol %, 0.082 g, 0.582mmol) in EtOH (5 mL) was added a solution of1-((2R,4S)-4-azido-2-ethylpyrrolidin-1-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine(0.115 g, 0.388 mmol, prepared using E from(2R,4S)-tert-butyl-4-azido-2-ethylpyrrolidine-1-carboxylate (synthesizedas described in. J. Med. Chem. 1988, 31, 1598-1611) with HCl, J withExample #5, Step C, OO, D with NaOH) in EtOH (2 mL). The reactionmixture was sparged with hydrogen and an atmosphere of hydrogen wasmaintained via balloon. After about 2 h the reaction mixture wasfiltered and 5-chloropyrazine-2-carbonitrile (0.013 g, 0.019 mmol,ArkPharm) was added. The reaction mixture was heated at about 70° C.After about 7 h the reaction mixture was cooled to ambient temperatureand diluted with water (5 mL). The resulting precipitate was collectedby filtration to provide the product as the free base. The solid wasdissolved in EtOAc (5 mL) and oxalic acid dihydrate (0.054 g, 0.43 mmol)was added. The solids were sonicated briefly with gentle heating. Aftercooling to ambient temperature, the solids were collected by filtrationand dried in vacuo to provide5-((3S,5R)-5-ethyl-1-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrrolidin-3-ylamino)pyrazine-2-carbonitrileoxylate, (0.100 g, 56%) as a tan solid: LC/MS (Table 1, Method a)R_(t)=1.80 min; MS m/z: 374 (M+H)⁺.

Example #27*N-((3S,5R)-5-ethyl-1-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrrolidin-3-yl)-3,3,3-trifluoropropane-1-sulfonamide

To slurry of palladium hydroxide on carbon (20 mol %, 0.013 g, 0.019mmol) in EtOH (5 mL) was added a solution of1-((2R,4S)-4-azido-2-ethylpyrrolidin-1-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine(0.110 g, 0.371 mmol, prepared using E from(2R,4S)-tert-butyl-4-azido-2-ethylpyrrolidine-1-carboxylate (synthesizedas described in. J. Med. Chem. 1988, 3/, 1598-1611) with HCl, J withExample #5, Step C, OO, D with NaOH) in EtOH (2 mL). The reactionmixture was sparged with hydrogen and an atmosphere of hydrogen wasmaintained via balloon. After about 2 h the reaction mixture wasfiltered and concd under reduced pressure The residue was dissolved inDCM (5 mL) and 3,3,3-trifluoropropane-1-sulfonyl chloride (0.080 g, 0.41mmol, Matrix) was added. After about 15 h additional3,3,3-trifluoropropane-1-sulfonyl chloride (80 mg, 0.408 mmol, Matrix)was added. After about 2 days the reaction mixture was partitionedbetween EtOAc (10 mL) and brine (10 mL). The organic layer wasseparated, dried over anhydrous Na₂SO₄, filtered, and concd underreduced pressure. The crude product was purified by chromatography onsilica gel eluting with EtOAc to provideN-((3S,5R)-5-ethyl-1-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrrolidin-3-yl)-3,3,3-trifluoropropane-1-sulfonamide(0.025 g, 16%) as a brown solid: LC/MS (Table 1, Method a) R_(t)=1.81min; MS m/z: 431 (M+H)⁺.

Example #281-cyclohexyl-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h][1,6]naphthyridine

Step A: ethyl4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution of4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (3.03 g, 9.81mmol, Adesis) in THF (49 mL) at about −78° C. was added sec-BuLi (1.4 Min cyclohexane, 15.4 mL, 21.6 mmol) dropwise. The reaction was stirredat about −78° C. for about 1 h before ethyl chloroformate (2.36 mL, 24.5mmol) was added rapidly. The reaction mixture was allowed to warm toambient temperature and was stirred for about 40 min. The reaction wasquenched with saturated aqueous NH₄Cl (25 mL). EtOAc (50 mL) and water(50 mL) were added and the layers were separated. The aqueous layer wasextracted with EtOAc (2×20 mL) and the combined organic layers werewashed with brine (2×20 mL). The organics were dried over anhydrousNa₂SO₄, filtered, and concd to dryness under reduced pressure to give ayellow oil. The oil was purified by silica gel chromatography elutingwith a gradient of 0-10% EtOAc in heptane to give ethyl4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(3.78 g, 98%) as a yellow oil: LC/MS (Table 1, Method b) R_(t)=3.98 min;MS m/z: 381 (M+H)⁺.

Step B: ethyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution of ethyl4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(4.30 g, 11.3 mmol) in THF (57 mL) at about 0° C. was added TBAF (1.0 Min THF, 12.6 mL, 12.6 mmol) dropwise and the reaction mixture wasstirred at about 0° C. for about 1 h. The reaction was warmed to roomtemperature and stirred for about 30 min. The solvent was removed underreduced pressure and the resulting oil was partitioned between EtOAc andbrine (100 mL each). The organic layer was dried over anhydrous Na₂SO₄,filtered and concd under reduced pressure. The residue was trituratedwith DCM and filtered to give ethyl4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (1.32 g, 52%) as an offwhite solid: LC/MS (Table 1, Method b) R_(t)=2.07 min; MS m/z: 225(M+H)⁺.

Step C: ethyl 4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution of ethyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(1.32 g, 5.88 mmol) in DMF (39 mL) at about 0° C. was added sodiumhydride (60% dispersion in mineral oil, 0.400 g, 10.00 mmol) and thereaction mixture was stirred at this temperature for about 15 min. Asolution of 4-methylbenzene-1-sulfonyl chloride (2.24 g, 11.8 mmol) inDMF (17 mL) was added dropwise and the reaction mixture was allowed towarm to ambient temperature for about 2 h. The reaction mixture wasconcd under reduced pressure and the residue was partitioned betweenEtOAc and water (25 mL each). The aqueous layer was extracted with EtOAc(2×25 mL) and the combined organic layers were washed with brine, driedover anhydrous MgSO₄, filtered, and concd under reduced pressure. Thesolid was triturated with heptane, and the precipitates were filtered togive ethyl 4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(2.28 g, 102%, 90% purity) as a white solid: LCMS (Table 1, Method c)R_(t)=1.64 min; MS m/z: 379 (M+H)⁺.

Step D: ethyl4-(cyclohexylamino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution of ethyl4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (2.28 g, 5.42mmol) in n-BuOH (21 mL) was added cyclohexanamine (1.24 mL, 10.8 mmol).The resulting solution was heated at about 110° C. for about 18 h. Thereaction mixture was cooled to ambient temperature and diluted withwater and DCM (50 mL each). The layers were separated and the organiclayer was dried over anhydrous Na₂SO₄, filtered, and concd to drynessunder reduced pressure. The residue was triturated with heptane and theprecipitates were filtered to give ethyl4-(cyclohexylamino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(1.74 g, 73%) as a light yellow solid: LC/MS (Table 1, Method b)R_(t)=3.18 min; MS m/z: 442 (M+H)⁺.

Step E:(4-(cyclohexylamino)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methanol

To a solution of ethyl4-(cyclohexylamino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(1.71 g, 3.88 mmol) in toluene (43.1 mL) at about −78° C. was addedDIBAL-H (1 M in hexanes, 6.60 mL, 6.60 mmol) dropwise. The reaction wasstirred for about 1 h at about −78° C. and the reaction mixture waswarmed to ambient temperature and stirred for about 1 h. The reactionwas quenched with saturated aqueous potassium sodium tartrate (15 mL)and the mixture was stirred for about 1 h. EtOAc (25 mL) was added andthe layers were separated. The organic layer was dried over anhydrousNa₂SO₄, filtered through a pad of silica gel while washing with EtOAc(20 mL), and the filtrate was concd under reduced pressure. The residuewas purified by silica gel chromatography eluting with a gradient of0-50% EtOAc in DCM to give(4-(cyclohexylamino)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methanol(1.24 g, 80%) as an off white solid: LC/MS (Table 1, Method b)R_(t)=2.51 min; MS m/z: 400 (M+H)⁺.

Step F:4-(cyclohexylamino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde

A mixture of(4-(cyclohexylamino)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methanol(1.12 g, 2.80 mmol) and manganese dioxide (5.48 g, 63.1 mmol) inchloroform (70 mL) was stirred at ambient temperature for about 18 h.The reaction mixture was diluted with chloroform (100 mL) and thereaction mixture was filtered through a pad of Celite® while washingwith chloroform (50 mL). The filtrate was concd under reduced pressureto give4-(cyclohexylamino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde(0.975 g, 87%) as an off white solid: LC/MS (Table 1, Method c)R_(t)=1.70 min; MS m/z: 398 (M+H)⁺.

Step G:(E/Z)-5-(2-(1,3-dioxolan-2-yl)vinyl)-N-cyclohexyl-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-amine

An oven dried flask under nitrogen was charged with((1,3-dioxolan-2-yl)methyl)triphenylphosphonium bromide (2.23 g, 5.19mmol) and THF (14 mL). The flask was cooled to about 0° C. in an icebath and potassium tert-butoxide (0.591 g, 5.00 mmol) was added. Themixture was stirred for about 30 min at about 0° C. and a solution of4-(cyclohexylamino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde(0.750 g, 1.89 mmol) in THF (4 mL) was added dropwise over about 10 min.The reaction was allowed to warm to ambient temperature and stirred forabout 16 h. Water (10 mL) was added and the reaction mixture wasextracted with Et₂O (3×10 mL). The combined organic extracts were driedover anhydrous Na₂SO₄, filtered, and concd under reduced pressure. Thecrude oil was purified by silica gel chromatography eluting 0-50% EtOAcin DCM to give5-(2-(1,3-dioxolan-2-yl)vinyl)-N-cyclohexyl-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-amine(0.590 g, 67%) as a mixture of E and Z isomers: LC/MS (Table 1, Methodc) R_(t)=1.69 min, 1.73 min; MS m/z: 468 (M+H)⁺, 468 (M+H)⁺.

Step H:5-(2-(1,3-dioxolan-2-yl)ethyl)-N-cyclohexyl-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-amine

To a solution of(E/Z)-5-(2-(1,3-dioxolan-2-yl)vinyl)-N-cyclohexyl-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-amine(0.512 g, 1.10 mmol) in EtOAc (19 mL) was added palladium on carbon (10mol %, 0.092 g, 0.086 mmol). The reaction mixture was purged withhydrogen and left under a hydrogen atmosphere using a balloon for about1.5 h. The reaction mixture was filtered through a pad of Celite® whilewashing with EtOAc (10 mL) and the filtrate was concd under reducedpressure to give5-(2-(1,3-dioxolan-2-yl)ethyl)-N-cyclohexyl-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-amine(0.499 g, 97%) as an off white foam: LC/MS (Table 1, Method b)R_(t)=2.84 min; MS m/z: 470 (M+H)⁺.

Step I:1-cyclohexyl-7-tosyl-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]-[1,6]naphthyridine

To a solution of5-(2-(1,3-dioxolan-2-yl)ethyl)-N-cyclohexyl-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-amine(0.209 g, 0.445 mmol) in EtOH (2 mL) was added aqueous HCl (12 N, 0.186mL, 2.23 mmol) dropwise. The mixture was heated at about 40° C. forabout 2 h and then cooled to about 0° C. in an ice bath. Sodiumborohydride (0.118 g, 3.12 mmol) was added portionwise and the mixturewas warmed to ambient temperature. After about 2 h the solvent wasremoved under reduced pressure and the residue was partitioned betweenEtOAc and saturated aqueous NaHCO₃ (10 mL each). The aqueous phase wasextracted with EtOAc (2×5 mL) and the combined organics were washed withwater and brine (5 mL each), dried over anhydrous Na₂SO₄, filtered andconcd under reduced pressure. The residue was purified by silica gelchromatography eluting with 0-50% EtOAc in heptane to give1-cyclohexyl-7-tosyl-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]-[1,6]naphthyridine(0.138 g, 75%) as a white solid: LC/MS (Table 1, Method b) R_(t)=3.01min; MS m/z: 410 (M+H)⁺.

Step J:1-cyclohexyl-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h][1,6]naphthyridine

To a solution of1-cyclohexyl-7-tosyl-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h][1,6]naphthyridine(0.132 g, 0.323 mmol) in 1,4-dioxane (2.2 mL) was added aqueous NaOH (2N, 0.32 mL, 0.65 mmol). The reaction was heated at about 80° C. forabout 96 h. Aqueous NaOH (5 N, 0.129 mL, 0.646 mmol) was added and thereaction was continued at about 80° C. for about 18 h. Aqueous NaOH (5N, 0.065 mL, 0.323 mmol) was added and the reaction mixture was heatedat about 100° C. for about 4 h. The reaction was cooled to ambienttemperature, EtOAc and water were added (5 mL each) and the layers wereseparated. The aqueous layer was extracted with EtOAc (2×5 mL) and thecombined organics were washed with water and brine (5 mL each), driedover anhydrous Na₂SO₄, filtered, and concd under reduced pressure. Theresidue was purified by silica gel chromatography eluting with agradient of 0-100% (95/4.5/0.5) DCM/MeOH/DEA in DCM to give1-cyclohexyl-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h][1,6]naphthyridine(0.052 g, 64%) as a tan solid: LC/MS (Table 1, Method b) R_(t)=1.88 min;MS m/z: 256 (M+H)⁺.

Example #29N-(4-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)bicyclo[2.2.2]octan-1-yl)cyclopropanesulfonamide

Step A: methyl4-(tert-butoxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylate

To a solution of 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylicacid (7.25 g, 34 2 mmol, Prime Organics) in toluene (150 mL) was addedDPPA (7.37 mL, 34.2 mmol) and TEA (4.76 mL, 34.2 mmol) and the reactionmixture was stirred at ambient temperature for about 1 h. The reactionmixture was then heated at about 110° C. for about 1 h and tert-butanol(16.1 mL, 171 mmol) was added and the reaction was heated at about 110°C. for about 14 h. The reaction was cooled to ambient temperature andwashed with saturated aqueous NaHCO₃ (2×50 mL) and brine (50 mL). Theorganics were dried over anhydrous Na₂SO₄, filtered and concd underreduced pressure. The crude material was purified by silica gelchromatography eluting with a gradient of 0-10% MeOH in DCM to givemethyl 4-(tert-butoxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylate(4.18 g, 43%) as a white solid: ¹H NMR (400 MHz, CDCl₃) δ 4.32 (s, 1H),3.63 (s, 3H), 1.95-1.76 (m, 12H), 1.42 (s, 9H).

Step B: methyl4-(benzyl(tert-butoxycarbonyl)amino)bicyclo[2.2.2]octane-1-carboxylate

To a solution of methyl4-(tert-butoxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylate (2.50 g,8.82 mmol) in DMF (42 mL) at about 0° C. was added sodium hydride (60%dispersion in mineral oil, 0.706 g, 17.6 mmol). The reaction mixture wasstirred for about 30 min at about 0° C. and THAI (0.652 g, 1.76 mmol)and benzyl bromide (2.10 mL, 17.7 mmol) were added. The reaction waswarmed to ambient temperature and continued to stir for about 5 h. Thesolvent was removed under reduced pressure and the residue was taken upin DCM (50 mL) and water (30 mL). The layers were separated and theorganic phase was washed with brine (30 mL), dried over anhydrous MgSO₄,filtered and concd under reduced pressure. The resulting oil waspurified by silica gel chromatography eluting with a gradient of 0-30%EtOAc in heptane to give methyl4-(benzyl(tert-butoxycarbonyl)amino)bicyclo[2.2.2]octane-1-carboxylate(2.71 g, 82%) as a clear colorless oil: LC/MS (Table 1, Method b)R_(t)=3.09 min; MS m/z: 374 (M+H)⁺.

Step C: tert-butylbenzyl(4-(hydroxymethyl)bicyclo[2.2.2]octan-1-yl)carbamate

To a solution of methyl4-(benzyl(tert-butoxycarbonyl)amino)bicyclo[2.2.2]octane-1-carboxylate(2.70 g, 7.23 mmol) in THF (24 mL) at about 0° C. was added lithiumborohydride (0.350 g, 14.46 mmol). The reaction mixture was warmed toambient temperature and stirred for about 16 h. The reaction was cooledto about 0° C. and water (15 mL) was carefully added. The reactionmixture was warmed to ambient temperature and was diluted with EtOAc (20mL). The layers were separated and the organic layer was washed withbrine (2×20 mL), dried over anhydrous Na₂SO₄, filtered and concd underreduced pressure to provide tert-butylbenzyl(4-(hydroxymethyl)bicyclo[2.2.2]octan-1-yl)carbamate (2.31 g, 92%)as an off white sticky foam: LC/MS (Table 1, Method b) R_(t)=2.67 min;MS m/z: 346 (M+H)⁺.

Step D: tert-butyl benzyl(4-formylbicyclo[2.2.2]octan-1-yl)carbamate

To a solution of tert-butylbenzyl(4-(hydroxymethyl)bicyclo[2.2.2]octan-1-yl) carbamate (2.30 g,6.66 mmol) in DCM (17 mL) was added Dess-Martin periodinane (4.24 g,9.99 mmol). After about 4 h, the reaction mixture was diluted with DCM(20 mL) and washed with saturated aqueous NaHCO₃ (2×30 mL), brine (30mL), dried over anhydrous MgSO₄, filtered, and concd under reducedpressure. The resulting oil was purified by silica gel chromatographyeluting with a gradient of 0-40% EtOAc in heptane to give tert-butylbenzyl(4-formylbicyclo[2.2.2]octan-1-yl)carbamate (1.10 g, 48%) as aclear colorless oil: LC/MS (Table 1, Method b) R_(t)=2.97 min; MS m/z:344 (M+H)⁺.

Step E: tert-butylbenzyl(4-((5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)(hydroxy)methyl)bicyclo[2.2.2]octan-1-yl)carbamate

To a solution of5-chloro-4-iodo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (1.33 g,3.06 mmol, Adesis) in THF (25 mL) at about −78° C. was added n-BuLi (1.6M solution in hexanes, 2.00 mL, 3.20 mmol) at such a rate that theinternal temperature did not exceed about −70° C. The reaction mixturewas stirred for about 45 min and a solution of tert-butylbenzyl(4-formylbicyclo[2.2.2]octan-1-yl)carbamate (1.05 g, 3.06 mmol) inTHF (6 mL) was added dropwise. The reaction mixture was stirred at about−78° C. for about 1 h and was slowly warmed to ambient temperature andstirred for about 1 h. Saturated aqueous NH₄Cl and EtOAc (10 mL each)were added and the layers were separated. The aqueous phase wasextracted with EtOAc (2×10 mL) and the combined organics were washedwith brine (10 mL), dried over anhydrous MgSO₄, filtered, and concdunder reduced pressure. The remaining oil was purified by silica gelchromatography eluting with a gradient of 0-40% EtOAc in heptane to givetert-butylbenzyl(4-((5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)(hydroxy)methyl)bicyclo[2.2.2]octan-1-yl)carbamate(1.27 g, 64%) as a clear colorless oil: LC/MS (Table 1, Method o)R_(t)=3.78 min; MS m/z: 652 (M+H)⁺.

Step F: tert-butylbenzyl(4-(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine-4-carbonyl)bicyclo[2.2.2]octan-1-yl)carbamate

To a solution of tert-butylbenzyl(4-(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)(hydroxy)methyl)bicyclo[2.2.2]octan-1-yl)carbamate(1.26 g, 1.93 mmol) in DCM (10 mL) was added Dess-Martin periodinane(1.64 g, 3.86 mmol). The reaction was stirred at ambient temperature forabout 3 h and was diluted with DCM (10 mL). The mixture was washed withsaturated aqueous NaHCO₃ (2×15 mL), brine (15 mL), dried over anhydrousMgSO₄, filtered, and concd under reduced pressure. The resulting oil waspurified by silica gel chromatography eluting with a gradient of 0-25%EtOAc in heptane to give tert-butylbenzyl(4-(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine-4-carbonyl)-bicyclo[2.2.2]octan-1-yl)carbamate(0.965 g, 77%) as a yellow oil: ¹H NMR (400 MHz, CDCl₃) δ 8.15 (s, 1H),7.32-7.24 (m, 3H), 7.23-7.08 (m, 3H), 6.23 (d, J=3.5, 1H), 4.53 (s, 2H),2.13-2.03 (m, 6H), 1.95 1.83 (m, 6H), 1.81-1.74 (m, 3H), 1.41 (s, 9H),1.12-1.06 (m, 18H).

Step G: tert-butylbenzyl(4-((5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)-(hydrazono)-methyl)bicyclo[2.2.2]octan-1-yl)carbamate

To a solution of tert-butylbenzyl(4-((5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)(hydrazono)methyl)bicyclo[2.2.2]octan-1-yl)carbamate(0.765 g, 1.18 mmol) in EtOH (4 mL) were added hydrazine (1.85 mL, 58.8mmol) and AcOH (0.337 mL, 5.88 mmol). The mixture was heated at about80° C. for about 6 days. The reaction was cooled to ambient temperatureand the solvent was removed under reduced pressure. EtOAc and water (5mL each) were added and the layers were separated. The organic layer waswashed with brine (5 mL), dried over anhydrous MgSO₄, filtered, andconcd under reduced pressure. The oil was purified by silica gelchromatography eluting with a gradient of 0-10% MeOH in DCM to givetert-butylbenzyl(4-(5-chloro-1H-pyrrolo[2,3-b]pyridin-4-)(hydrazono)methyl)bicyclo[2.2.2]octan-1-yl)carbamate(0.631 g, 84%, 95% purity) as an off white solid: LC/MS (Table 1, Methodb) R_(t)=2.72 min, MS m/z: 508 (M+H)⁺.

Step H: tert-butylbenzyl(4-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine-1-yl)bicycle[2.2.2]octan-1-yl)carbamate

A microwave reaction vial was charged with tert-butylbenzyl(4-((5-chloro-1H-pyrrolo[2,3-b]pyridin-4-)(hydrazono)methyl)bicyclo[2.2.2]octan-1-yl)carbamate (0.700 g, 1.38 mmol) and NMP (11 mL). Sodium tert-butoxide(0.331 g, 3.44 mmol), palladium acetate (0.031 g, 0.14 mmol) and(R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyl-di-tert-butylphosphine(0.076 g, 0.14 mmol) were each added sequentially in one portion to thesolution. The reaction mixture was heated in a Biotage microwave atabout 150° C. for about 2 h (250 psi maximum pressure, 1 min ramp, 150max watts). The reaction mixture was filtered through a pad of Celite®while washing with EtOAc (15 mL), and the filtrate was concd underreduced pressure. The remaining material was transferred to a microwavevial and sodium tert-butoxide (0.331 g, 3.44 mmol), palladium acetate(0.031 g, 0.138 mmol) and(R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]-ethyl-di-tert-butylphosphine(0.076 g, 0.138 mmol) were added. The reaction mixture was heated in aBiotage microwave at about 160° C. for about 2 h (250 psi maximumpressure, 1 min ramp, 150 max watts). The reaction mixture was filteredthrough a pad of Celite® while washing with EtOAc (20 mL). Water (15 mL)was added and the layers were separated. The aqueous layer was extractedwith EtOAc (2×10 mL) and the combined organic layers were washed withwater (3×10 mL) and brine (5×15 mL), dried over anhydrous MgSO₄,filtered, and concd under reduced pressure. The dark residue waspurified by silica gel chromatography eluting with a gradient of 10-100%EtOAc in heptane to give tert-butylbenzyl(4-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine-1-yl)bicycle[2.2.2]octan-1-yl)carbamate(0.281 g, 40%) as a light brown solid: LC/MS (Table 1, Method b)R_(t)=2.57 min; MS m/z: 472 (M+H)⁺.

Step I:N-benzyl-4-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine-1-yl)bicyclo[2.2.2]octan-1-aminehydrochloride

To a solution of tert-butylbenzyl(4-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)bicyclo[2.2.2]octan-1-yl)carbamate(0.280 g, 0.543 mmol) in 1,4-dioxane (4 mL) was added aqueous HCl (4 Min 1,4-dioxane, 0.58 mL, 2 3 mmol) and the reaction mixture was stirredat about 60° C. for about 2 h. The reaction was cooled to ambienttemperature and the precipitates were filtered while washing with aminimal amount of Et₂O. The solid was dried under vacuum to giveN-benzyl-4-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine-1-yl)bicyclo[2.2.2]octan-1-aminehydrochloride (0.216 g, 98%) as a tan solid: LC/MS (Table 1, Method b)R_(t)=1.46 min; MS m/z: 372 (M+H)⁺.

Step J:4-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)bicyclo[2.2.2]octan-1-amine

To a solution ofN-benzyl-4-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)bicyclo[2.2.2]octan-1-aminehydrochloride (0.150 g, 0.368 mmol) in MeOH (6 mL) was added ammoniumformate (0.116 g, 1.84 mmol) and 20% PdOH₂ on carbon (0.039 g, 0.055mmol). The reaction mixture was heated at about 65° C. for about 2 h.The reaction mixture was filtered through a pad of Celite® while washingwith EtOAc (about 10 mL) and the solvent was removed under reducedpressure. Water and EtOAc (10 mL each) were added and the layers wereseparated. The aqueous layer was extracted with EtOAc (5×5 mL) and thecombined organics were dried over anhydrous MgSO₄, filtered, and concdunder reduced pressure to give4-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)bicyclo[2.2.2]octan-1-amine(0.073 g, 71%) as an off white foam: LC/MS (Table 1, Method b)R_(t)=1.08 min; MS m/z: 282 (M+H)⁺.

Step K:N-(4-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)bicyclo[2.2.2]octan-1-yl)cyclopropanesulfonamide

To a mixture of4-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)bicyclo[2.2.2]octan-1-amine(0.075 g, 0.267 mmol) in DMF (2.5 mL) was added TEA (0.06 mL, 0.40 mmol)and cyclopropanesulfonyl chloride (0.027 mL, 0.27 mmol, Matrix). Thereaction mixture was stirred at ambient temperature for about 16 h.Cyclopropanesulfonyl chloride (0.014 mL, 0.133 mmol, Matrix) was addedto the reaction mixture and the reaction continued to stir at ambienttemperature for about 4 h. The reaction mixture was diluted with water(10 mL) and extracted with DCM (3×10 mL). The combined organic layerswere washed with brine (10 mL), dried over anhydrous Na₂SO₄, filtered,and concd under reduced pressure. The residue was purified by silica gelchromatography eluting with a gradient of 0-10% MeOH in DCM to giveN-(4-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)bicyclo[2.2.2]octan-1-yl)cyclopropanesulfonamide(0.015 g, 15%) as a white solid: LC/MS (Table 1, Method b) R_(t)=1.72min; MS m/z: 386 (M+H)⁺.

Example #30 and 311-((1S,2S,4R)-2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridineand1-((1R,2R,4S)-2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine

Step A: tert-butyl 2-ethyl-4-(4-methoxybenzyloxy)cyclopentanecarboxylate

To a solution of ethyl2-ethyl-4-(4-methoxybenzyloxy)cyclopentanecarboxylate (39.8 g, 130 mmol,Preparation #EE.1 predominantly 1S,2R,4S and 1R,2S,4R) in EtOH (286 mL)was added aqueous NaOH (2 N, 572 mL, 1140 mmol). The reaction mixturewas stirred at about 50° C. for about 16 h. The reaction mixture wascooled to ambient temperature and the organic solvent was removed underreduced pressure. The aqueous layer was washed with Et₂O (2×300 mL),cooled to about 0° C. in an ice bath and acidified to about pH 1 withaqueous HCl (5 N). The aqueous suspension was extracted with EtOAc(2×400 mL). The combined organics were washed with brine (200 mL), driedover anhydrous MgSO₄, filtered, and concd to give 34.5 g of crude solid.To a solution of the crude carboxylic acid (15.0 g, 53.9 mmol) in DMF(216 mL) was added iodomethane (6.71 mL, 108 mmol) and K₂CO₃ (14.9 g,108 mmol). The reaction mixture was stirred at ambient temperature forabout 48 h. Water and EtOAc (250 mL each) were added and the layers wereseparated. The aqueous layer was extracted with EtOAc (2×250 mL) and thecombined organics were washed with water (250 mL), brine (3×250 mL),dried over anhydrous MgSO₄, filtered, and concd under reduced pressure.The oil was purified by silica gel chromatography eluting with agradient of 0-50% EtOAc in heptane to give the methyl ester (14.1 g,48.1 mmol) as a yellow oil. To a solution of methyl ester (14.1 g, 48.1mmol) in THF (160 mL) was added potassium tert-butoxide (16.2 g, 144mmol) and the reaction mixture was stirred at ambient temperature forabout 18 h. Saturated aqueous NH₄Cl (100 mL) was added and the reactionmixture was diluted with EtOAc (100 mL). The layers were separated andthe organics were washed with brine (50 mL), dried over anhydrous MgSO₄,filtered and concd under reduced pressure. The remaining oil waspurified by silica gel chromatography eluting with a gradient of 0-40%EtOAc in heptane to give tert-butyl2-ethyl-4-(4-methoxybenzyloxy)cyclopentanecarboxylate (11.7 g, 73%,predominantly 1R,2R,4S and 1S,2S,4R) as a clear colorless oil: LC/MS(Table 1, Method c) R_(t)=1.95 min; MS m/z: 335 (M+H)⁺.

Step B: 2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)methanol

To a solution of tert-butyl2-ethyl-4-(4-methoxybenzyloxy)cyclopentanecarboxylate (11.7 g, 35.0mmol) in THF (175 mL) at to about 0° C. was added LAH (2 M in THF, 17.5mL, 35 0 mmol) dropwise and the reaction mixture was slowly warmed toambient temperature and stirred for about 1.5 h. The reaction was cooledto about 0° C. in an ice bath and quenched by a successive addition ofwater (150 mL dropwise), aqueous NaOH (1 N, 150 mL) and water (100 mL).The resulting mixture was warmed to ambient temperature and stirred forabout 30 min. The mixture was filtered through a pad of Celite® whilewashing with Et₂O (500 mL). The filtrate layers were separated. Theorganic layer was washed with brine (2×200 mL), dried over anhydrousMgSO₄, filtered, and concd under reduced pressure to give2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)methanol (8.62 g, 93%) as ayellow oil: LC/MS (Table 1, Method b) R_(t)=2.29 min; MS m/z: 265(M+H)⁺.

Step C: 2-ethyl-4-(4-methoxybenzyloxy)cyclopentanecarbaldehyde

To a solution of 2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)methanol(8.60 g, 32 5 mmol) in DCM (163 mL) was added Dess-Martin periodinane(20.7 g, 48.8 mmol). The reaction mixture was stirred at ambienttemperature for about 2.5 h. The reaction mixture was diluted with DCM(100 mL), washed with saturated aqueous NaHCO₃ (2×150 mL) and brine (150mL), dried over anhydrous MgSO₄, filtered, and concd under reducedpressure. The resulting oil was purified by silica gel chromatographyeluting with a gradient of 0-50% EtOAc in heptane to give2-ethyl-4-(4-methoxybenzyloxy)cyclopentanecarbaldehyde (6.93 g, 81%) asa yellow oil: LC/MS (Table 1, Method b) R_(t)=2.59 min; MS m/z: 263(M+H)⁺.

Step D:(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)methanol

To a solution of5-chloro-4-iodo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (4.99 g,11.5 mmol, Adesis) in THF (90 mL) at about −78° C. was added n-BuLi (1.6M solution in hexanes, 10.7 mL, 17.2 mmol) at such a rate that theinternal temperature did not exceed about −70° C. After stirring forabout 45 min at about −78° C. a solution of2-ethyl-4-(4-methoxybenzyloxy)cyclopentanecarbaldehyde (3.00 g, 11.4mmol) in THF (22 mL) was added dropwise and the reaction mixture wasstirred at about −78° C. for about 1 h. The reaction was slowly warmedto ambient temperature and stirred for about 0.5 h. The reaction mixturewas cooled to about −78° C., saturated aqueous NH₄Cl (40 mL) was added,and the mixture was warmed to rt. Water (10 mL) was added and the layerswere separated. The aqueous phase was extracted with EtOAc (3×50 mL).The combined organics were washed with brine (50 mL), dried overanhydrous MgSO₄, filtered and concd under reduced pressure. The crudeoil was purified by silica gel chromatography eluting with a gradient of0-40% EtOAc in heptane to give(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)methanol(4.47 g, 68%, 92% purity) as a yellow oil: LC/MS (Table 1, Method o)R_(t)=2.64 min; MS m/z: 571 (M+H)⁺.

Step E:(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)methanone

To a solution of(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)methanone(4.47 g, 7.20 mmol) in DCM (40 mL) was added Dess-Martin periodinane(4.58 g, 10.8 mmol). The reaction mixture was stirred at ambienttemperature for about 90 min. The reaction was diluted with DCM (40 mL),washed with saturated aqueous NaHCO₃ (2×60 mL), brine (40 mL), driedover anhydrous MgSO₄, filtered, and concd under reduced pressure. Thecrude material was purified by silica gel chromatography eluting with agradient of 0-40% EtOAc in heptane to give(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-ethyl-4-(4-methoxybenzyloxy)-cyclopentyl)methanone(3.32 g, 81%) as a yellow oil: LC/MS (Table 1, Method o) R_(t)=3.04 min;MS m/z: 569 (M+H)⁺.

Step F:5-chloro-4-2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)-(hydrazono)methyl)-1H-pyrrolo[2,3-b]pyridine

To a solution of(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)methanone(1.01 g, 1.77 mmol) in EtOH (5.5 mL) were added hydrazine (2.78 mL, 89.0mmol) and AcOH (0.508 mL, 8.87 mmol). The reaction mixture was heated atabout 80° C. for about 18 h. The reaction was cooled to ambienttemperature and the solvent was removed under reduced pressure. Water(20 mL) and EtOAc (25 mL) were added and the layers were separated. Theorganic layer was washed with saturated aqueous NaHCO₃ and brine (15 mLeach), dried over anhydrous MgSO₄, filtered and concd under reducedpressure. The crude oil was purified silica gel chromatography elutingwith a gradient of 0-10% MeOH in DCM to give5-chloro-4-((2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)-(hydrazono)methyl)-1H-pyrrolo[2,3-b]pyridine(0.354 g, 47%) as a yellow foam: LC/MS (Table 1, Method b) R_(t)=2.40min, MS m/z: 427 (M+H)⁺.

Step G:1-((1S,2S,4R)-2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridineand1-((1R,2R,4S)-2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine

A microwave reaction vial was charged with5-chloro-4-((2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)(hydrazono)methyl)-1H-pyrrolo[2,3-b]pyridine(0.900 g, 2.11 mmol) and NMP (14.1 mL). Sodium tert-butoxide (0.506 g,5.27 mmol), palladium(II) acetate (0.047 g, 0.211 mmol) and((R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyl-di-tert-butylphosphine(0.117 g, 0.211 mmol) were added sequentially and the mixture was heatedin a microwave at about 150° C. for about 1 h (250 psi maximum pressure,1 min ramp, 150 max watts). EtOAc (20 mL) was added and the mixture wasfiltered through a pad of Celite® while washing with EtOAc (20 mL).Water (15 mL) was added and the layers were separated. The aqueous layerwas extracted with EtOAc (2×10 mL), the combined organics were washedwith water (3×10 mL), brine (5×10 mL), dried over anhydrous MgSO₄,filtered and concd under reduced pressure. The residue was purified bysilica gel chromatography eluting with a gradient of 40-100% EtOAc inheptane followed by purification using General Procedure AA to give1-((1S,2S,4R)-2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridineor1-((1R,2R,4S)-2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine(0.065 g, 8%, Table 2, Method 35, R_(t)=20.0 min, or =positive) and1-((1S,2S,4R)-2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridineor1-((1R,2R,4S)-2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine(0.058 g, 7%, Table 2, Method 35, R_(t)=23.4 min, or =negative): LC/MS(Table 1, Method b) R_(t)=2.26 min; MS m/z: 391 (M+H)⁺.

Example #32N-cyano-N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide

To the solution ofN-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide(0.05 g, 0.134 mmol, WO2009152133) in DMF (4 mL), KOH (0.022 g, 0.401mmol) was added and the mixture was stirred at rt for about 5 min. Tosylcyanide (0.024 g, 0.134 mmol) was added and stirring was continued forabout 2 h. The solvent was removed under reduced pressure and theresidue purified by preparative HPLC (Table 1, Method q) to yieldN-cyano-N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide(0.0025 g, 5%) as an off-white solid: LC/MS (Table 1, Method a)R_(t)=1.84 min; MS m/z: 400 (M+H)⁺.

Example #33*N-((1S,3R,4S)-3-ethyl-4-(2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h][1,6]naphthyridin-1-yl)cyclopentyl)cyclopropanesulfonamide

Step A: 4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde

To a suspension of 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde(2.00 g, 11.1 mmol, Adesis) in DMF (30 mL) was added NaH (60% dispersionin mineral oil, 0.500 g, 12 5 mmol) forming a yellow solution. Thereaction mixture was stirred at ambient temperature for about 30 minthen 4-methylbenzene-1-sulfonyl chloride (2.40 g, 12.6 mmol) was added.The reaction mixture was stirred at ambient temperature for about 30 minand poured into ice water (about 50 mL). The solid was collected viavacuum filtration, while washing with water (about 15 mL), and dried ina vacuum oven to give4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (3.22 g, 87%)as an off white solid: LC/MS (Table 1, Method b) R_(t)=2.56 min; MS m/z:335 (M+H)⁺.

Step B:(E/Z)-5-(2-(1,3-dioxolan-2-yl)vinyl)-4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine

A round bottom flask was charged with((1,3-dioxolan-2-yl)methyl)triphenylphosphonium bromide (5.29 g, 12.3mmol) and THF (29.0 mL). The flask was cooled to about 0° C. in an icebath and potassium tert-butoxide (1.38 g, 12.3 mmol) was added. Themixture was stirred for about 30 min at about 0° C. and a suspension of4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (1.50 g, 4.48mmol) in THF (8.30 mL) was added dropwise. The reaction was warmed toambient temperature and stirred for about 16 h. Aqueous sodium hydroxide(2 M, 4.50 mL, 9.00 mmol) was added and the reaction mixture was heatedto about 55° C. for about 1 h. Water and ether (10 mL each) were addedand the layers were separated. The aqueous phase was extracted withether (3×10 mL), the combined organics were dried over anhydrous Na₂SO₄and filtered. About 50% of the solvent was removed under reducedpressure and the remaining organic was filtered through silica gelwashing with ether (about 15 mL). The filtrate was concentrated underreduced pressure. The residue was purified by silica gel chromatographyeluting with a gradient of 0-50% EtOAc in DCM to give a white solid. Thesolid was dissolved in DMF (12 mL) and NaH (60% dispersion in mineraloil, 0.179 g, 4.49 mmol) was added. The reaction mixture was stirred atambient temperature for about 30 min then 4-methylbenzene-1-sulfonylchloride (0.684 g, 3.59 mmol) was added. The reaction was stirred atambient temperature for about 30 min and poured into ice water (about 30mL). EtOAc (30 mL) was added and the layers were separated. The aqueousphase was further extracted with EtOAc (2×30 mL) and the combinedorganics were washed with brine (2×20 mL), dried over anhydrous MgSO₄,filtered and concentrated under reduced pressure. The resulting oil waspurified by silica gel chromatography eluting with a gradient of 0-50%EtOAc in heptane to give(E/Z)-5-(2-(1,3-dioxolan-2-yl)vinyl)-4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine(0.90 g, 50%) as an off white foam: LC/MS (Table 1, Method b) R_(t)=2.65min; MS m/z: 405 (M+H)⁺ and R_(t)=2.70 min; MS m/z: 405 (M+H)⁺.

Step C:5-(2-(1,3-dioxolan-2-yl)ethyl-4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine

A mixture of(E/Z)-5-(2-(1,3-dioxolan-2-yl)vinyl)-4-chloro-1-tosyl-1-pyrrolo[2,3-b]pyridine(0.900 g, 2.22 mmol) and 10 wt % Pd/C (0.118 g, 0.111 mmol) was purgedwith N₂ and evacuated under vacuum (3×). After the third evacuationEtOAc (23 mL) was added. The flask was purged with N₂ and evacuatedunder vacuum (3×). After the 3rd evacuation the flask was placed under ahydrogen atmosphere for about 1 h. The hydrogen atmosphere was replacedwith N₂ and the reaction mixture was filtered through a pad of Celite®washing with EtOAc (about 10 mL) and the filtrate was concentrated underreduce pressure to give5-(2-(1,3-dioxolan-2-yl)ethyl)-4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine(0.530 g, 59%) as a thick oil which solidified upon standing: LC/MS(Table 1, Method b) R_(t)=2.71 min; MS m/z: 407 (M+H)⁺.

Step D: 3-(4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)propanal

To a solution of5-(2-(1,3-dioxolan-2-yl)ethyl)-4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine(0.520 g, 1.28 mmol) in THF (4.2 mL) was added aqueous HCl (6 M, 0.639mL, 3.83 mmol). The reaction mixture was stirred at ambient temperaturefor about 2 h and was heated to about 50° C. for about 1 h. The reactionwas cooled to ambient temperature and water (0.64 mL) was added and thereaction stirred for about 16 h. The pH was adjusted to about 7 withsaturated aqueous NaHCO₃ and EtOAc (about 10 mL) was added. The layerswere separated and the aqueous phase was extracted with EtOAc (10 mL).The combined organics were dried over anhydrous MgSO₄, filtered andconcentrated under reduced pressure. Acetone (12 mL) and pyridiniump-toluenesulfonate (0.096 g, 0.383 mmol) were added. The reaction washeated at reflux for about 2 h. The reaction was cooled to ambienttemperature and concentrated under reduced pressure. The residue waspurified by silica gel chromatography eluting with a gradient of 0-50%EtOAc in DCM to give3-(4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)propanal (0.44 g, 84%,90% purity) as an off white foam: LC/MS (Table 1, Method b) R_(t)=2.50min; MS m/z: 363 (M+H)⁺.

Step E:N-((1S,3S,4R)-3-(3-(4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)propylamino)-4-ethylcyclopentyl)cyclopropanesulfonamide

To a mixture of3-(4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)propanal (0.420 g,1.04 mmol) andN#1S,3S,4R)-3-amino-4-ethylcyclopentyl)cyclopropanesulfonamide (0.290 g,1.25 mmol, prepared using OOO from Example #23 step E with NaOH) in DCE(4.00 mL) was added glacial acetic acid (0.089 mL, 1.6 mmol). Thereaction mixture stirred for about 15 min at ambient temperature andsodium triacetoxyborohydride (0.331 g, 1.56 mmol) was added. Thereaction was left stirring at ambient temperature for about 72 h.Saturated aqueous NaHCO₃ (about 5 mL) was slowly added followed by DCM(5 mL). The layers were separated and the aqueous phase was extractedwith DCM (2×5 mL). The combined organics were dried over anhydrousMgSO₄, filtered and concentrated under reduced pressure. The remainingyellow oil was purified by silica gel chromatography eluting with agradient of 0-50% EtOAc in heptane to giveN-((1S,3S,4R)-3-(3-(4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)propylamino)-4-ethylcyclopentyl)cyclo-propanesulfonamide(0.330 g, 55%) as a white foam: LC/MS (Table 1, Method b) R_(t)=2.10min; MS m/z: 579 (M+H)⁺.

Step F:N-((1S,3R,4S)-3-ethyl-4-(7-tosyl-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h][1,6]naphthyridin-1-yl)cyclopentyl)cyclopropanesulfonamide

A microwave vial was charged with a solution ofN-((1S,3S,4R)-3-(3-(4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)propylamino)-4-ethylcyclopentyl)cyclopropanesulfonamide(0.200 g, 0.345 mmol) in 1-propanol (1.70 mL). DIEA (0.180 mL, 1.04mmol) and potassium iodide (0.057 g, 0.345 mmol) were added and thereaction mixture was heated in a Biotage® microwave at about 150° C. forabout 30 min. The reaction was resubmitted to microwave heating at about180° C. for about 1 h. The reaction was resubmitted to microwave heatingat about 180° C. for about 10 h. The reaction mixture was transferred toa round bottom flask and silica gel (about 1 g) was added. The solventwas removed under reduced pressure and the resulting silica gel mixturewas purified by silica gel chromatography eluting with a gradient of0-10% MeOH in DCM to giveN-((1S,3R,4S)-3-ethyl-4-(7-tosyl-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h][1,6]naphthyridin-1-yl)cyclopentyl)cyclopropanesulfonamide(0.050 g, 27%) as a yellow foam: LC/MS (Table 1, Method b) R_(t)=2.52min; MS m/z: 543 (M+H)⁺.

Step G:N-((1S,3R,4S)-3-ethyl-4-(2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h][1,6]naphthyridin-1-yl)cyclopentyl)cyclopropanesulfonamide

To a solution ofN-((1S,3R,4S)-3-ethyl-4-(7-tosyl-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h][1,6]naphthyridin-1-yl)cyclopentyl)cyclopropanesulfonamide(0.041 g, 0.076 mmol) in 1,4-dioxane was added aqueous NaOH (5 N, 0.106mL, 0.529 mmol). The reaction was heated to about 80° C. for about 16 h.The reaction mixture was cooled to ambient temperature and water (5 mL)and EtOAc (10 mL) were added. The layers were separated and the aqueousphase was extracted with EtOAc (2×10 mL). The combined organics weredried over anhydrous MgSO₄, filtered, and concentrated under reducedpressure. The residue was purified by silica gel chromatography elutingwith a gradient of 0-10% MeOH in DCM to giveN-((1S,3R,4S)-3-ethyl-4-(2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h][1,6]naphthyridin-1-yl)cyclopentyl)cyclopropane-sulfonamide(0.02 g, 72%) as a white solid: LC/MS (Table 1, Method a) R_(t)=1.48min; MS m/z: 389 (M+H)⁺.

Example #34*N-((1S,3S,4R)-3-(2,3-dihydrodipyrrolo[2,3-b:2′,3′-d]pyridin-1(6H)-yl)-4-ethylcyclopentyl)cyclopropanesulfonamide

Step A: 4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde

To a suspension of 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde(2.00 g, 11.1 mmol, Adesis) in DMF (30 mL) was added NaH (60% dispersionin mineral oil, 0.500 g, 12 5 mmol) forming a yellow solution. Thereaction mixture was stirred at ambient temperature for about 30 minthen 4-methylbenzene-1-sulfonyl chloride (2.40 g, 12.6 mmol) was added.The reaction mixture was stirred at ambient temperature for about 30 minand poured into ice water (about 50 mL). The solid was collected viavacuum filtration, while washing with water (about 15 mL), and dried ina vacuum oven to give4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (3.22 g, 87%)as an off white solid: LC/MS (Table 1, Method b) R_(t)=2.56 min; MS m/z:335 (M+H)⁺.

Step B:(E/Z)-4-chloro-5-(2-methoxyvinyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine

To a suspension of (methoxymethyl)triphenylphosphonium chloride (1.28 g,3.73 mmol) in THF (14.8 mL) at about 0° C. was added dropwise potassiumtert-butoxide (1 M solution in THF, 3.70 mL, 3.70 mmol). The reactionmixture was stirred for about 30 min at about 0° C. and a suspension of4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (1.00 g, 2.99mmol) in THF (1.80 mL) was added. The reaction mixture was warmed toambient temperature and stirred for about 4 h. The reaction wasneutralized with 1 M aqueous HCl and then EtOAc and water (10 mL each)were added. The layers were separated and the aqueous phase wasextracted with EtOAc (2×10 mL). The combined organics were dried overanhydrous MgSO₄, filtered and concentrated under reduced pressure. Theremaining solid was purified by silica gel chromatography eluting with agradient of 0-50% EtOAc in heptane to give(E/Z)-4-chloro-5-(2-methoxyvinyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(0.96 g, 89%) as an off white solid: LC/MS (Table 1, Method b)R_(t)=2.83 min; MS m/z: 363 (M+H)⁺ and R_(t)=2.86 min; MS m/z: 363(M+H)⁺

Step C:N-((1S,3S,4R)-3-(2-(4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)ethylamino)-4-ethylcyclopentyl)cyclopropanesulfonamide

To a mixture of(E/Z)-4-chloro-5-(2-methoxyvinyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(0.95 g, 2.62 mmol) in THF (26 mL) was added aqueous HCl (1 M, 6.55 mL,6.55 mmol). The reaction mixture was heated at reflux for about 16 h.The reaction was cooled to ambient temperature and the pH was adjustedto about 7 with saturated aqueous NaHCO₃. DCM (about 30 mL) was addedand the layers were separated. The aqueous phase was extracted with DCM(2×20 mL). The combined organics were dried over anhydrous Na₂SO₄,filtered, and concentrated under reduced pressure. The residue was takenup in DCE (13 mL) andN-((1S,3S,4R)-3-amino-4-ethylcyclopentyl)cyclopropanesulfonamide (0.608g, 2.62 mmol, prepared using OOO from Example #23 step E with NaOH) andglacial acetic acid (0.150 mL, 2.62 mmol) were added. Sodiumtriacetoxyborohydride (0.832 g, 3.93 mmol) was added and the reactionwas left stirring at ambient temperature for about 16 h. The reactionwas diluted with DCM (20 mL) and saturated aqueous NaHCO₃ (20 mL) wasadded. The layers were separated and the aqueous phase was extractedwith DCM (2×10 mL). The combined organics were washed with brine (10mL), dried over anhydrous MgSO₄, filtered and concentrated under reducedpressure. The residue was purified by silica gel chromatography elutingwith a gradient of 25-100% EtOAc in heptane to give N-((1S,3S,4R)-3-(2-(4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)ethylamino)-4-ethylcyclopentyl)cyclopropanesulfonamide(0.45 g, 30%) as an off white solid: LC/MS (Table 1, Method a)R_(t)=1.87 min; MS m/z: 565 (M+H)⁺.

Step D:N-((1S,3S,4R)-3-(2,3-dihydrodipyrrolo[2,3-b:2′,3′-d]pyridin-1(6H)-yl)-4-ethylcyclopentyl)cyclopropanesulfonamide

A microwave vial was charged with a solution ofN-((1S,3S,4R)-3-(2-(4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)ethylamino)-4-ethylcyclopentyl)cyclopropanesulfonamide(0.350 g, 0.619 mmol) in 1-propanol (3.2 mL). DIPEA (0.324 mL, 1.86mmol) and potassium iodide (0.154 g, 0.929 mmol) were added and thereaction was heated in a Biotage® microwave for about 10 h at about 180°C. EtOAc and water (10 mL each) were added to the reaction mixture andthe layers were separated. The aqueous phase was extracted with EtOAc(2×10 mL). The combined organics were dried over anhydrous MgSO₄,filtered and concentrated under reduced pressure. The residue waspurified by silica gel chromatography eluting with a gradient of 0-100%DCM/MeOH/Et2NH (950/45/5) in DCM and the solvent was removed underreduced pressure. The solid was further purified by preparative HPLC(Table 1, Method w) to give to giveN-((1S,3S,4R)-3-(2,3-dihydrodipyrrolo[2,3-b:2′,3′-d]pyridin-1(6H)-yl)-4-ethylcyclopentyl)cyclopropanesulfonamidewith 30 mol % ammonium acetate as an excipient (0.099 g, 38%) as a whitesolid: LC/MS (Table 1, Method a) R_(t)=1.70 min; MS m/z: 375 (M+H)⁺.

Example #35 and #35.11-((1S,2R,4S)-4-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-2-ethylcyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineand1-((1S,2R,4S)-4-(5-cyclopropyl-1H-1,2,4-triazol-1-yl)-2-ethylcyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine

Step A: ethyl 8-ethyl-1,4-dioxaspiro[4.4]nonane-7-carboxylate

A round bottom flask was charged with ethyl2-ethyl-4-oxocyclopentanecarboxylate (1.5 g, 8.1 mmol, Example #22, StepB) in DCM (22 mL). To the flask were added ethylene glycol (0.91 mL, 16mmol), triethylorthoformate (2.0 mL, 12 mmol), and p-toluenesulfonicacid monohydrate (0.31 g, 1.6 mmol). The reaction mixture was stirred atrt for about 24 h. The solution was concd under reduced pressure to givebrown oil that was dissolved in EtOAc and purified by silica gelchromatography eluting with a gradient of 0-50% EtOAc in heptane. Theproduct containing fractions were combined and concd to dryness underreduced pressure to give ethyl8-ethyl-1,4-dioxaspiro[4,4]nonane-7-carboxylate as a light yellow oil(1.6 g, 83%): LC/MS (Table 1, Method c) MS m/z 229 (M+H)⁺; ¹H NMR (CDCl)δ 4.14 (q, 2H), 3.90 (m, 4H), 2.99 (q, 1H), 2.32-2.27 (m, 1H), 2.26-2.11(m, 1H), 2.05-1.99 (m, 1H), 1.96-1.91 (m, 1H), 1.83-1.78 (m, 1H),1.46-1.39 (m, 1H), 1.31-1.24 (m, 1H), 1.26 (t, 3H), 0.90 (t, 3H).

Step B: 8-ethyl-1,4-dioxaspiro[4.4]nonane-7-carboxylic acid

A round bottom flask was charged with ethyl8-ethyl-1,4-dioxaspiro[4.4]nonane-7-carboxylate (0.32 g, 1.4 mmol) andsodium hydroxide (aqueous 1 N, 14.0 mL, 14.0 mmol). The solution wasstirred overnight at rt. To the solution was added DCM (30 mL) followedby the addition of 20% aqueous citric acid (about 20 mL) to reach pH ofabout 2. The layers were separated and the aqueous solution wasextracted with DCM (2×30 mL) and DCM/EtOAc (1:1, 30 mL). The combinedextracts were dried over anhydrous MgSO₄, filtered, and concd underreduced pressure to give 8-ethyl-1,4-dioxaspiro[4,4]nonane-7-carboxylicacid as a clear, colorless oil (0.27 g, 96%): LC/MS (Table 1, Method c)R_(t)=1.20 min; MS m/z: 201 (M+H)⁺.

Step C:8-ethyl-N′-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,4-dioxaspiro[4.4]nonane-7-carbohydrazide

A 50 mL round bottom flask was charged with2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (0.350 g, 1.16 mmol,Example #1, Step D), 8-ethyl-1,4-dioxaspiro[4.4]nonane-7-carboxylic acid(0.250 g, 1.25 mmol), and DCM (6.0 mL). To the reaction mixture wasadded HATU (0.483 g, 1.27 mmol) and TEA (0.64 mL, 4 6 mmol) and theresulting yellow suspension was stirred at rt for about 3 h. To thereaction solution was added DCM (25 mL) and the solution was washed withwater and brine (20 mL each). The organic layer was dried over anhydrousMgSO₄, filtered, and concd under reduced pressure to give a brown oil.The crude product was purified by silica gel chromatography eluting witha gradient of: 0-10% MeOH in DCM. The product containing fractions wereconcd under reduced pressure to give8-ethyl-N′-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,4-dioxaspiro[4.4]nonane-7-carbohydrazideas a foam (0.50 g, 89%): LC/MS (Table 1, Method c) R_(t)=1.49 min; MSm/z: 486 (M+H)⁺.

Step D:1-(8-ethyl-1,4-dioxaspiro[4.4]nonan-7-yl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine

A round bottom flask was charged with8-ethyl-N-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,4-dioxaspiro[4.4]nonane-7-carbohydrazide(4.90 g, 10.1 mmol) and 1,4-dioxane (50 mL). To the flask was added DIEA(8.81 mL, 50.5 mmol) followed by the addition of thionyl chloride (0.770mL, 10.6 mmol). The mixture was heated to about 75° C. for about 90 min.Additional thionyl chloride (0.074 mL, 1.0 mmol) was added and heatingwas continued for about 1 h. The reaction was cooled to rt and stirredovernight. The solution was diluted with DCM (75 mL) and washed withwater (50 mL). The layers were separated and the organic layer was driedover anhydrous MgSO₄, filtered, and concd under reduced pressure to givea dark brown oil. The crude product was purified via flash silica gelchromatography eluting with a gradient of 0-60% acetone in heptane. Theproduct containing fractions were combined and concd to give materialthat was loaded onto a second column eluting with a gradient of 0-60%acetone in heptane. The product containing fractions were combined andconcd under reduced pressure to give1-(8-ethyl-1,4-dioxaspiro[4.4]nonan-7-yl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineas a tan powder (3.0 g, 64%): LC/MS (Table 1, Method c) R_(t)=1.44 min;MS m/z: 468 (M+H)⁺.

Step E:1-(8-ethyl-1,4-dioxaspiro[4.4]nonan-7-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine

To the solution of1-(8-ethyl-1,4-dioxaspiro[4.4]nonan-7-yl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine(3.76 g, 8.04 mmol) in 1,4-dioxane (55 mL), aqueous sodium hydroxidesolution (2N, 12 mL) was added and the reaction mixture was heated atabout 60° C. for about 90 min. The solvent was removed and the residuepartitioned between saturated solution of ammonium chloride in water andEtOAc (75 mL each). The aqueous phase was further washed with EtOAc (60mL); the combined organic extracts were washed with brine (65 mL), driedover anhydrous magnesium sulfate, filtered, and concentrated to yield abrown solid. The solid was triturated in ether (20 mL) and theprecipitate was collected by filtration and dried to yield1-(8-ethyl-1,4-dioxaspiro[4.4]nonan-7-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine(2.22 g, 88%) as a beige solid. LC/MS (Table 1, Method a) R_(t)=1.71min; MS m/z: 314 (M+H)⁺.

Step F:1-(8-ethyl-1,4-dioxaspiro[4.4]nonan-7-yl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine

To a suspension of sodium hydride (60% dispersion in mineral oil, 0.355g, 8.87 mmol) in DMF (45 mL), the solution of1-(8-ethyl-1,4-dioxaspiro[4.4]nonan-7-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine(2.78 g, 8.87 mmol) in DMF (45 mL) was added dropwise at about 0° C. andthe resulting solution was stirred at this temperature for about 20 min.SEM Cl (1.75 mL, 8.87 mmol) was added dropwise and the resulting mixturewas stirred overnight while being gradually warmed up. The solvent wasremoved under reduced pressure and the residue was partitioned betweenEtOAc and water (120 mL each). The aqueous phase was further washed withEtOAc (50 mL); the combined organic extracts were washed with brine (100mL), dried over anhydrous magnesium sulfate, filtered, and concentratedto yield1-(8-ethyl-1,4-dioxaspiro[4.4]nonan-7-yl)-6-((2-(trimethylsilyl)ethoxy)-methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine(3.87 g, 98%) as a brown amorphous solid. LC/MS (Table 1, Method a)R_(t)=2.49 min; MS m/z: 444 (M+H)⁺.

Step G:3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanone

To a solution of1-(8-ethyl-1,4-dioxaspiro[4.4]nonan-7-yl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine(3.87 g, 8.72 mmol) in THF (30 mL), was added aqueous HCl (1N, 26.2 mL)at about 0° C. The ice bath was removed and the reaction was stirred atambient temperature for about 6 h. THF was removed under reducedpressure. The aqueous phase was neutralized by the addition of saturatedaqueous NaHCO₃ and was extracted with EtOAc (2×50 mL). The combinedorganic extracts were washed with brine (60 mL), dried over anhydrousMgSO₄, filtered, and concentrated. The residue was purified by silicagel column chromatography using 20 to 80% EtOAc in DCM to yield3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanone(2.84 g, 81%) as a yellow amorphous solid. LC/MS (Table 1, Method a)R_(t)=2.44 min; MS m/z: 400 (M+H)⁺.

Step H:3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanone

A solution of3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanone(0.296 g, 0.741 mmol) in THF (2.96 mL) was cooled to about 0° C. and toit was added DIBAL-H (1M in cyclohexane, 1.482 mL, 1.482 mmol). Thereaction was stirred for about 45 min. The reaction was quenched withMeOH (3 mL). To the reaction mixture was added saturated aqueous NH₄Cl(10 mL) and EtOAc (10 mL). The organic layer was collected and washedwith brine (10 mL), dried over anhydrous MgSO₄, filtered andconcentrated under reduced pressure to provide the crude material. Thecrude material was purified by silica gel column chromatography using0-5% MeOH/CH₂Cl₂ to provide a scalemic mixture enriched in(1S,3R,4S)-3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanol(148 mg, 0.369 mmol, 50%) and a scalemic mixture enriched in(1R,3R,4S)-3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanol(60 mg, 0.149 mmol, 20%) both as amorphous solids. LC/MS (Table 1,Method a) R_(t)=2.37 min; MS m/z: 402 (M+H)⁺ and R_(t)=2.16 min; MS m/z:402 (M+H)⁺ respectively.

Step I:3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylmethanesulfonate

To a solution of the scalemic mixture enriched in(1R,3R,4S)-3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanol(0.5 g, 1.245 mmol) and TEA (0.347 mL, 2.49 mmol) in DCM (13 mL) wasadded MsCl (0.107 mL, 1.37 mmol) dropwise, and the reaction mixture wasstirred at room temperature overnight. The solvent was removed underreduced pressure and the residue purified by silica gel columnchromatography using 10 to 70% EtOAc in DCM to yield3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylmethanesulfonate (0.48 g, 80%) as a white amorphous solid. LC/MS (Table1, Method a) R_(t)=2.54 min; MS m/z: 480 (M+H)⁺

Step J:1-((1S,2R,4S)-4-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-2-ethylcyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineand1-((1S,2R,4S)-4-(5-cyclopropyl-1H-1,2,4-triazol-1-yl)-2-ethylcyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]

To a solution of 3-cyclopropyl-1H-1,2,4-triazole (0.054 g, 0.494 mmol)in DMF (3 mL), sodium hydride (0.019 g, 0.486 mmol, 60% dispersion inmineral oil) was added at about 0° C. and the reaction mixture wasstirred for about 10 min. The temperature was raised to about 50° C. and3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylmethanesulfonate (0.079 g, 0.165 mmol) was added. The reaction mixturewas stirred at about 75° C. overnight. The solvent was removed underreduced pressure and the residue partitioned between water and EtOAc (10mL each). The aqueous phase was further washed with EtOAc (7 mL); thecombined extracts were washed with brine (10 mL), dried over anhydrousMgSO₄, filtered and concentrated under reduced pressure to yield amixture of1-(4-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-2-ethylcyclopentyl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineand1-(4-(5-cyclopropyl-1H-1,2,4-triazol-1-yl)-2-ethylcyclopentyl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine.This mixture was dissolved in DCM (3 mL) and 2 mL of trifluoroaceticacid was added. The resulting mixture was stirred at ambient temperaturefor about 2 h. The solvents were removed under reduced pressure. Theresidue was dissolved in 1,4-dioxane (3 mL); 2 mL of concentrated NH₄OH(4 mL) solution in water was added. The mixture was heated at about 60°C. for about 2 hours. The solvents were removed under reduced pressureand the residue was purified by HPLC (Table 2, Method 32) to yield1-((1S,2R,4S)-4-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-2-ethylcyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine(0.028 g, 25% yield) [Example #35] and1-((1S,2R,4S)-4-(5-cyclopropyl-1H-1,2,4-triazol-1-yl)-2-ethylcyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine(0.013 g, 12% yield) [Example #35.1] both as white solids. LC/MS (Table1, Method a) R_(t)=1.74 min; MS m/z: 363 (M+H)⁺ and LC/MS (Table 1,Method a) R_(t)=1.73 min; MS m/z: 363 (M+H)⁺

Examples #36 and #37(3S,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideand(3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

Step A: (Z)-ethyl pent-2-enoate

To a slurry of Lindlar catalyst (0.844 g, 0.396 mmol) in THF (100 mL)and pyridine (10.00 mL) was added ethyl pent-2-ynoate (5.22 mL, 39.6mmol). The reaction mixture was sparged with hydrogen for about 10 minand an atmosphere of hydrogen was maintained via balloon. After about 15h the reaction mixture was filtered through a pad of Celite®, dilutedwith Et₂O (30 mL) and washed with saturated aqueous CuSO₄ (40 mL),followed by water (40 mL). The organic layer was separated, dried overanhydrous MgSO₄, filtered, and concd in vacuo to provide crude (Z)-ethylpent-2-enoate (5 g, 98%). ¹H NMR (DMSO-d₆) δ 1.05 (t, 3H), 1.28 (t, 3H),2.65 (m, 2H), 4.18 (q, 2H), 5.72 (m, 1H), 6.21 (m, 1H).

Step B: (cis)-ethyl 1-benzyl-4-ethylpyrrolidine-3-carboxylate

To a solution ofN-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (9.98 mL, 39.0mmol) and (Z)-ethyl pent-2-enoate (5 g, 39.0 mmol) in DCM (50 mL) wasadded TFA (0.030 mL, 0.390 mmol) at rt. After about 2 days, the reactionmixture was concd in vacuo to provide crude (cis)-ethyl1-benzyl-4-ethylpyrrolidine-3-carboxylate (9.8 g, 96%) as an oil. LC/MS(Table 1, Method a) R_(t)=1.62 min; MS m/z: 262 (M+H)⁺.

Step C: (cis)-ethyl 4-ethylpyrrolidine-3-carboxylate

A parr shaker was charged with PdOH₂ on carbon (2.243 g, 3.19 mmol) and(cis)-ethyl 1-benzyl-4-ethylpyrrolidine-3-carboxylate (16.7 g, 63.9mmol) followed by EtOH (100 mL). The reaction mixture was degassed andpurged with hydrogen gas and shaken on the parr shaker at 60 psi forabout 4 days at ambient temperature. The reaction mixture was degassedand purged with nitrogen. The suspension was filtered through a pad ofCelite® washing with EtOH (900 mL). The solvent was removed underreduced pressure to afford (cis)-ethyl 4-ethylpyrrolidine-3-carboxylate(8.69 g, 79%) as an oil: LC/MS (Table 1, Method a) R_(t)=1.11 min; MSm/z: 172 (M+H)⁺.

Step D: (cis)-1-(tert-butoxycarbonyl)-4-ethylpyrrolidine-3-carboxylicacid

To a flask charged with (cis)-ethyl 4-ethylpyrrolidine-3-carboxylate(8.69 g, 50 7 mmol) was added aqueous HCl (6N, 130 mL, 782 mmol). Thesolution was heated at about 75° C. for about 12 h. aqueous HCl (6N, 100mL, 599 mmol) was added and stirred at about 80° C. for about 20 h.Aqueous HCl (6N, 100 mL, 599 mmol) was added and continued stirring atabout 80° C. for about 20 h. The reaction mixture was cooled to ambienttemperature and the solvent was removed under reduced pressure.1,4-Dioxane (275 mL) and water (50 mL) were added followed byportionwise addition of Na₂CO₃ (13.5 g, 127 mmol). Di-tert-butyldicarbonate (13.3 g, 60.9 mmol) was added and the reaction mixture wasstirred at ambient temperature for about 16 h. The solid was filteredand washed with EtOAc (250 mL). The aqueous layer was acidified withaqueous HCl (1N) to about pH 3-4. The layers were partitioned and theaqueous layer was extracted with EtOAc (3×100 mL). The combined organiclayers were dried over anhydrous Na₂SO₄, filtered and removed underreduced pressure. As the organic layer was almost fully concentrated(about 10 mL remaining), a solid precipitated. Heptane (30 mL) was addedand the solid was filtered washing with heptane to afford(cis)-1-(tert-butoxycarbonyl)-4-ethylpyrrolidine-3-carboxylic acid (3.9g, 32%) as an off white solid as product: LC/MS (Table 1, Method c)R_(t)=0.57 min; MS m/z: 242 (M−H)⁻.

Step E: (cis)-tert-butyl3-ethyl-4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)pyrrolidine-1-carboxylate

To a suspension of 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (5.00g, 16.48 mmol, Example 1, Step D) and(cis)-1-(tert-butoxycarbonyl)-4-ethylpyrrolidine-3-carboxylic acid (4.01g, 16.48 mmol) in DCM (70 mL) were added TEA (5.75 mL, 41.2 mmol) andHATU (6.90 g, 18.15 mmol, Novabiochem). The resulting suspension wasstirred at about 25° C. for about 2 h. The reaction mixture wastransferred to a separatory funnel and washed with saturated aqueousNaHCO₃ (4×30 mL). The organic layer was dried over anhydrous MgSO₄,filtered, and concd in vacuo to give a brown foam. The crude materialwas purified via flash chromatography on silica gel by dry loading thecompound onto the column and eluting with 50-100% EtOAc in DCM/petroleumether (1:1) to afford (cis)-tert-butyl3-ethyl-4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)pyrrolidine-1-carboxylatewith EtOAc as an excipient (9.41 g, 100%) as a tan foam: LC/MS (Table 1,Method a) R_(t)=2.45 min; MS m/z: 529 (M+H)⁺.

Step F:1-((cis)-4-ethylpyrrolidin-3-yl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine

To a solution of (cis)-tert-butyl3-ethyl-4-(2-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)pyrrolidine-1-carboxylate(9.4 g, 16.41 mmol) in 1,4-dioxane (150 mL), TEA (7.00 mL, 50.2 mmol)and thionyl chloride (1.80 mL, 24 6 mmol) were each added sequentiallyin one portion to the solution. The reaction was heated at about 70° C.for about 18 h. The solvent was removed under reduced pressure. Asolution of HCl (4 M in 1,4-dioxane, 41.0 mL, 164 mmol) was added in oneportion and the reaction was stirred for about 3 h. Et₂O (100 mL) wasadded and the solid was filtered. The solids were combined with themother liquor and the solvent was removed under reduced pressure. Thesolid was partially dissolved in EtOAc (650 mL) and washed with aqueoussaturated NaHCO₃ (150 mL). An emulsion formed and was filtered throughCelite® washing with EtOAc. The solid on top of the Celite® layer wasproduct. The solid was scraped off of the Celite® and dissolved in asolution of 10% MeOH in DCM (150 mL). The organic layer was washed withwater (2×30 mL). The combined organic layers were washed with saturatedaqueous sodium bicarbonate (4×150 mL), dried over MgSO₄, filtered, andconcentrated under reduced pressure to afford1-((cis)-4-ethylpyrrolidin-3-yl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine(5.88 g, 80%) as a brown foam: LC/MS (Table 1, Method a) R_(t)=1.55 min;MS m/z: 411 (M+H)⁺.

Step G:(cis)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

To a solution of 2,2,2-trifluoroethanamine (0.080 g, 0.804 mmol) in DMF(3 mL) was added CDI (0.150 g, 0.926 mmol). The resulting solution wasstirred at about 65° C. for about 2 h.1-((cis)-4-ethylpyrrolidin-3-yl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine(0.250 g, 0.609 mmol) was added and the reaction continued stirring atabout 65° C. for about 2 h. The reaction was cooled to about ambienttemperature. The solvent was removed under reduced pressure. The crudematerial was purified by flash chromatography on silica gel eluting witha gradient of 0-10% MeOH in afford(cis)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide(0.306 g, 94%) as a brown residue: LC/MS (Table 1, Method a) R_(t)=2.19min; MS m/z: 536 (M+H)⁺.

Step H:(3S,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideand(3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

To a solution of(cis)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide(0.306 g, 0.571 mmol) in 1,4-dioxane (10 mL) was added aqueous NaOH (1N, 1.50 mL, 1.50 mmol). The reaction was heated at about 50° C. forabout 1 h. The layers were partitioned between DCM (25 mL) and water (10mL). The aqueous layer was acidified with 20% aqueous citric acid toabout pH 4 and extracted with DCM (4×25 mL). The combined organic layerswere dried over anhydrous MgSO₄, filtered, and concd under reducedpressure to give a brown residue. The crude material was purified byflash chromatography on silica gel eluting with a gradient of 0-10% MeOHin DCM to give a racemic mixture of products as a brown residue. Thecompound was further purified using chiral preparative HPLC (Table 2,Method 55) to afford(3S,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide(R_(t)=14.5 min, or =negative) (0.031 g, 14%)[Example #36]: LC/MS (Table1, Method a) R_(t)=1.62 min; MS m/z: 382 (M+H)¹ and(3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide(R_(t)=17.3 min, or =positive) (0.033 g, 15%) [Example #37]: LC/MS(Table 1, Method a) R_(t)=1.62 min; MS m/z: 382 (M+H)⁺.

Example #385-(((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methyl)-3-(methoxymethyl)-1,2,4-oxadiazole

Step A: ethyl 8-ethyl-1,4-dioxaspiro[4.4]nonane-7-carboxylate

A round bottom flask was charged with ethyl2-ethyl-4-oxocyclopentanecarboxylate (1.5 g, 8.1 mmol, Example #22, StepB) in DCM (22 mL). To the flask were added ethylene glycol (0.91 mL, 16mmol), triethylorthoformate (2.0 mL, 12 mmol) and p-toluenesulfonic acidmonohydrate (0.31 g, 1.6 mmol). The reaction mixture was stirred at rtfor about 24 h. The solution was concd under reduced pressure to givebrown oil that was dissolved in EtOAc and purified by silica gelchromatography eluting with a gradient of 0-50% EtOAc in heptane. Theproduct containing fractions were combined and concd to dryness underreduced pressure to give ethyl8-ethyl-1,4-dioxaspiro[4,4]nonane-7-carboxylate as a light yellow oil(1.6 g, 83%): LC/MS (Table 1, Method c) MS m/z 229 (M+H)⁺; ¹H NMR (CDCl)δ 4.14 (q, 2H), 3.90 (m, 4H), 2.99 (q, 1H), 2.32-2.27 (m, 1H), 2.26-2.11(m, 1H), 2.05-1.99 (m, 1H), 1.96-1.91 (m, 1H), 1.83-1.78 (m, 1H),1.46-1.39 (m, 1H), 1.31-1.24 (m, 1H), 1.26 (t, 3H), 0.90 (t, 3H).

Step B: 8-ethyl-1,4-dioxaspiro[4.4]nonane-7-carboxylic acid

A round bottom flask was charged with ethyl8-ethyl-1,4-dioxaspiro[4.4]nonane-7-carboxylate (0.32 g, 1.4 mmol) andaqueous sodium hydroxide (1 N, 14.0 mL, 14.0 mmol). The solution wasstirred overnight at rt. To the solution was added DCM (30 mL) followedby the addition of 20% aqueous citric acid (about 20 mL) to reach pH ofabout 2. The layers were separated and the aqueous solution wasextracted with DCM (2×30 mL) and DCM/EtOAc (1:1, 30 mL). The combinedextracts were dried over anhydrous MgSO₄, filtered, and concd underreduced pressure to give 8-ethyl-1,4-dioxaspiro[4,4]nonane-7-carboxylicacid as a clear, colorless oil (0.27 g, 96%): LC/MS (Table 1, Method c)R_(t)=1.20 min; MS m/z: 201 (M+H)⁺.

Step C:8-ethyl-N′-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,4-dioxaspiro[4.4]nonane-7-carbohydrazide

A 50 mL round bottom flask was charged with2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (0.350 g, 1.16 mmol,Example #1, Step D), 8-ethyl-1,4-dioxaspiro[4.4]nonane-7-carboxylic acid(0.250 g, 1.25 mmol), and DCM (6.0 mL). To the reaction mixture wasadded HATU (0.483 g, 1.27 mmol) and TEA (0.64 mL, 4 6 mmol) and theresulting yellow suspension was stirred at rt for about 3 h. To thereaction solution was added DCM (25 mL) and the solution was washed withwater and brine (20 mL each). The organic layer was dried over anhydrousMgSO₄, filtered, and concd under reduced pressure to give a brown oil.The crude product was purified by silica gel chromatography eluting witha gradient of 0-10% MeOH in DCM over 25 min. to give8-ethyl-N′-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,4-dioxaspiro[4.4]nonane-7-carbohydrazideas a foam (0.50 g, 89%): LC/MS (Table 1, Method c) R_(t)=1.49 min; MSm/z: 486 (M+H)⁺.

Step D:1-(8-ethyl-1,4-dioxaspiro[4.4]nonan-7-yl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine

A round bottom flask was charged with8-ethyl-N′-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,4-dioxaspiro[4.4]nonane-7-carbohydrazide(4.90 g, 10.1 mmol) and 1,4-dioxane (50 mL). To the flask was added DIEA(8.81 mL, 50.5 mmol) followed by the addition of thionyl chloride (0.770mL, 10.6 mmol). The mixture was heated to about 75° C. for about 90 min.Additional thionyl chloride (0.074 mL, 1.0 mmol) was added and heatingwas continued for about 1 h. The reaction was cooled to rt and stirredovernight. The solution was diluted with DCM (75 mL) and washed withwater (50 mL). The layers were separated and the organic layer was driedover anhydrous MgSO₄, filtered, and concd under reduced pressure to givea dark brown oil. The crude product was purified via flash silica gelchromatography eluting with a gradient of 0-60% acetone in heptane. Theproduct containing fractions were combined and concd to give materialthat was loaded onto a second column eluting with a gradient of 0-60%acetone in heptane. The product containing fractions were combined andconcd under reduced pressure to give1-(8-ethyl-1,4-dioxaspiro[4.4]nonan-7-yl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineas a tan powder (3.0 g, 64%): LC/MS (Table 1, Method c) R_(t)=1.44 min;MS m/z: 468 (M+H)⁺.

Step E:3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanone

A round bottom flask was charged with1-((7S,8R)-8-ethyl-1,4-dioxaspiro[4.4]nonan-7-yl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine(3.56 g, 7.61 mmol) and THF (20 mL). To the solution was added aqueousHCl (6N, 3.81 mL, 22 8 mmol) and the mixture was stirred at rt for about2 h. The solvent was removed under reduced pressure and DCM (75 mL) andwater (50 mL) were added. The layers were separated and the organicsolution was dried over anhydrous MgSO₄, filtered, and concd underreduced pressure to give3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanoneas a brown foam (2.99 g, 93%): LC/MS (Table 1, Method c) R_(t)=1.40 min;MS m/z: 424 (M+H)⁺.

Step F: ethyl2-((cis)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylidene)acetate

To a slurry of sodium hydride (0.227 g, 5.67 mmol, 60% dispersion inoil) in THF (30 mL) was added ethyl 2-(diethoxyphosphoryl)acetate (1.18mL, 5.90 mmol). After about 30 min a solution of(cis)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanone(2.00 g, 4.72 mmol) in THF (1.0 mL) was added. After about 4 h EtOAc andsat NaHCO₃ were added. The organic layer was separated concd in vacuoand purified by flash chromatography on silica gel eluting with 20-100%EtOAc in DCM to afford ethyl2-((cis)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylidene)acetate(2.08 g 89%): LC/MS (Table 1, Method c) R_(t)=2.52-2.56 min; MS m/z: 494(M+H)⁺ as a mixture of diastereomers and ethyl2-((cis)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylidene)acetate(0.150 g, 9%), as a mixture of diastereomers: LC/MS (Table 1, Method a)R_(t)=1.85-1.89; MS m/z: 340 (M+H)⁺.

Step G: ethyl2-((cis)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylidene)acetate

To a solution of ethyl2-((cis)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylidene)acetate(1.9 g, 3.85 mmol) in THF (30 mL) at 0° C. was added a solution of TBAF(11.55 mL, 11.55 mmol, 1 M in THF). After about 10 min, TBAF (7.70 mL,7.70 mmol, 1 M in THF) was added. After about 1 h EtOAc and brine wereadded to the reaction mixture. After about one h the organic layer wasseparated, concd in vacuo and purified by flash chromatography on silicagel eluting with EtOAc to afford ethyl2-((cis)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylidene)acetate(1.3 g, 100%) as a mixture of diastereomers: LC/MS (Table 1, Method a)R_(t)=1.86-1.90 min; MS m/z: 340 (M+H)⁺.

Step H: ethyl2-((1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)acetateand2-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)acetate

To a slurry of PdOH₂ on carbon (0.134 g, 0.192 mmol) in THF (20 mL) wasadded a solution of ethyl2-((cis)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylidene)acetate(1.3 g, 3.83 mmol) in THF (5 mL). The reaction mixture was sparged withhydrogen and an atmosphere of hydrogen was maintained via balloon. Afterabout 3 days the reaction mixture was filtered through Celite®, concd invacuo and purified by flash chromatography on silica gel eluting withEtOAc to afford ethyl2-((cis)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)acetate(1.3 g, 99% yield) as a dark brown/black solid. The compound was furtherpurified by chiral preparative HPLC (Table 2, method 47) to afford ethyl2-((1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)acetate(R_(t)=12.0 min, or =negative) (0.400 g, 31%): LC/MS (Table 1, Method a)R_(t)=1.85 min; MS m/z: 342 (M+H)⁺ and ethyl2-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)acetate(R_(t)=13.7 min, or =negative) (0.420 g, 32%) as a white solid: LC/MS(Table 1, Method a) R_(t)=1.84 min; MS m/z: 342 (M+H)⁺.

Step I:5-(((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methyl)-3-(methoxymethyl)-1,2,4-oxadiazole

To a solution of ethyl2-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)acetate(0.100 g, 0.293 mmol) in toluene (0.20 mL) and MeOH (0.20 mL) was added(Z)—N-hydroxy-2-methoxyacetimidamide (0.300 g, 2.89 mmol, Tyger) andK₂CO₃ (0.100 g, 0.726 mmol). The solution was heated in a CEM microwaveat about 130° C. for about 1 h (250 psi maximum pressure, 1 min ramp,300 max watts). The solvent was removed under reduced pressure. Theresidue was diluted with DCM (3 mL) and a small amount of MeOH. Thecrude material was purified by flash chromatography on silica geleluting with a gradient of 0-10% MeOH in DCM. The residue was dissolvedin EtOAc and heptane was added. The solvent was concd. The solid wasdried in a heated vacuum oven (about 70° C.) for about 20 h to afford5-(((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methyl)-3-(methoxymethyl)-1,2,4-oxadiazole(0.062 g, 56%) as a white solid: LC/MS (Table 1, Method a) R_(t)=1.79min; MS m/z: 382 (M+H)⁺.

Example #39cis-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclohexanamine

Step A: ethyl 4-(dibenzylamino)cyclohexanecarboxylate

A 250 mL flask was charged with ethyl 4-oxocyclohexanecarboxylate (5 g,28 5 mmol, Alfa Aesar) and THF (75 mL). The solution was cooled to about0° C. and AcOH (2.28 mL, 39.9 mmol) and dibenzylamine (6.18 g, 31.3mmol) (TCI) were added dropwise, resulting in formation of a thicksuspension. Na(OAc)₃BH (14.3 g, 64.1 mmol) was added portionwise and thereaction mixture was stirred at ambient temperature for about 72 h. Thereaction mixture was cooled to about 10° C. Water (25 mL) was added andthe reaction mixture was stirred for about 15 min. Heptanes (50 mL) wereadded. The layers were separated and the organic layer was washed with10% aqueous AcOH solution (25 mL) and then with water (10 mL). Theorganic layer was extracted with 4% HCl solution twice (40 mL and 20mL). The combined aqueous layer was washed with heptanes (20 mL). To theaqueous layer was slowly added 30% aqueous K₂CO₃ solution (30 g) toadjust the pH to 10. The aqueous solution was extracted with heptanetwice (75 mL and 15 mL). The combined organic layer was washed withwater (30 mL). The organic layer was dried over anhydrous Na₂SO₄ andfiltered. The filtrate was concd under reduced pressure to give ethyl4-(dibenzylamino)cyclohexanecarboxylate (7.2 g, 72%) as an oil whichsolidified upon standing: LC/MS (Table 1, Method a) R_(t)=3.18 and 3.23min; MS m/z: 352 (M+H)⁺.

Step B: 4-(dibenzylamino)cyclohexanecarboxylic acid

To a 250 mL flask, ethyl 4-(dibenzylamino)cyclohexanecarboxylate (7.2 g,20 5 mmol) and a solution of conc. H₂SO₄ (7.64 mL, 143 mmol) in water(80 mL) were added. The reaction mixture was stirred at about 90° C. forabout 18 h, cooled to about 5° C. and the pH was adjusted to about 7with the addition of 50% aqueous NaOH. The aqueous solution wasextracted with ether (300 mL). The organic layer was dried overanhydrous Na₂SO₄, filtered and washed with ether. The filtrate was concdunder reduced pressure to give 4-(dibenzylamino)cyclohexanecarboxylicacid (5.6 g, 85%) as a solid: LC/MS (Table 1, Method b) R_(t)=1.65 min;MS m/z: 324 (M+H)⁺.

Step C: sulfoxonium, dimethyl-,2-(4-(dibenzylamino)cyclohexyl)-2-oxoethylide

To a 250 mL flask, 4-(dibenzylamino)cyclohexanecarboxylic acid (5.6 g,17.3 mmol), HATU (6.75 g, 17.4 mmol) and TEA (8.45 mL, 60 6 mmol) in THF(60 mL) were added to give a white suspension. The reaction mixture wasstirred at ambient temperature for about 1 h. To a 500 mL flask,trimethylsulfoxonium chloride (6.82 g, 51.9 mmol) and potassiumtert-butoxide (6.44 g, 54.5 mmol) in THF (60 mL) were added to give awhite suspension. The reaction mixture was stirred at about 65° C. forabout 3 h. The reaction mixture was cooled to about 5° C. The aboveactivated ester solution was added dropwise over about 50 min. Thereaction mixture was stirred at about 0-5° C. for about 90 min. Thereaction mixture was quenched by the addition of water (120 mL) dropwiseat about 0-5° C. over about 25 min. The quenched reaction mixture wasstirred at about 0-5° C. for about 30 min, then at ambient temperaturefor about 18 h. THF was removed under reduced pressure to give whitesuspension. The suspension was partitioned between EtOAc (300 mL) andwater (200 mL). The aqueous layer was extracted with EtOAc (2×100 mL).The combined organic layer was washed with water (50 mL) and brine (3×40mL). The organic layer was dried over anhydrous Na₂SO₄ and concd underreduced pressure. The residue was dissolved in hot MeOH (100 mL) andconcd under reduced pressure. The oil was dissolved in hot MeOH (60 mL)and concd under reduced pressure to give a white solid. The solid wasdissolved in MeOH (36 g) and water (12 g) at about 55° C. The solutionwas cooled to ambient temperature, then to about 5° C. Additional 3:1MeOH/water (40 mL) was added to the suspension. The suspension wasfiltered, washed with 1:1 MeOH/water (20 mL) and heptane (20 mL). Thecollected wet cake was dried at about 60° C. in a vacuum oven for about72 h to yield sulfoxonium, dimethyl-,2-(4-(dibenzylamino)cyclohexyl)-2-oxoethylide (5.44 g, 79%) as whitesolid: LC/MS (Table 1, Method a) R_(t)=1.42, 1.45 min; MS m/z 398(M+H)⁺.

Step D:1-(4-(dibenzylamino)cyclohexyl)-2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)ethanone

To a 100 mL 2-neck round-bottomed flask, sulfoxonium, dimethyl-,2-(4-(dibenzylamino)cyclohexyl)-2-oxoethylide (5.4 g, 13 6 mmol),5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-amine (4.7 g, 16.3 mmol, Preparation#E.1.1), and [Ir(COD)Cl]₂ (0.365 g, 0.543 mmol Alfa Aesar) were added.The reaction vessel was purged with N₂ for about 10 min. To the reactionvessel, pre-degassed DCE (25 mL) was added via syringe. The reactionmixture was purged with N₂ for about 10 min and stirred under N₂ atabout 70° C. for about 3 h. The reaction mixture was allowed to cool toambient temperature and concd under reduced pressure. The residue waspurified by silica gel flash chromatography eluting with a gradient of5-70% EtOAc:heptane to yield1-(4-(dibenzylamino)cyclohexyl)-2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)ethanone(5.8 g, 65%) as glassy solid: LC/MS (Table 1, Method a) R_(t)=3.24 and3.26 min; MS m/z 608 (M+H)⁺.

Step E:N,N-dibenzyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclohexanamine

A mixture of1-(4-(dibenzylamino)cyclohexyl)-2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)ethanone(5.8 g, 9.54 mmol) and PFPAA (23.7 g, 76 mmol) in MeCN (70 mL) washeated at about 50° C. for about 17 h. PFPAA (4.73 g, 15 2 mmol) wasadded and the reaction mixture was heated at about 60° C. for about 7 hand at ambient temperature for about 72 h. The solvent was removed underreduced pressure to yieldN,N-dibenzyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclohexanamine(11.3 g crude, but assumed 5.6 g, 100%) as a foam: LC/MS (Table 1,Method b) R_(t)=3.03 and 3.09 min; MS m/z 590 (M+H)⁺.

Step F:(cis)-N,N-dibenzyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclohexanamine

N,N-dibenzyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclohexanamine(5.6 g, 9.5 mmol) was dissolved in 1,4-dioxane (80 mL). Aqueous NaOH (2N, 47.5 mL, 95 mmol) was added and the reaction mixture was heated atabout 60° C. for about 120 min. The organic solvent was removed underreduced pressure and the residue was extracted with 2-methyltetrahydrofuran (300 mL). The aqueous layer was extracted with 2-methyltetrahydrofuran (3×50 mL). The combined organic extracts were washedwith brine (30 mL), dried over anhydrous Na₂SO₄ and concd under reducedpressure. To the residue was added EtOAc (500 mL). The solid was removedby filtration and the filtrate was dried over anhydrous Na₂SO₄ and concdunder reduced pressure. Purification by silica gel flash chromatographyeluting with a gradient of 1-8% MeOH in EtOAc yielded(cis)-N,N-dibenzyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclohexanamine(1.0 g, 24%): LC/MS (Table 1, Method a) R_(t)=2.48 min; MS m/z 436(M+H)⁺.

Step G:(cis)-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclohexanamine

To a mixture of(cis)-N,N-dibenzyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclohexanamine(1.0 g, 2.3 mmol) in EtOH (30 mL) was added Pd(OH)₂ on carbon (0.64 g,0.46 mmol) and the resulting mixture was shaken under hydrogen pressureof about 30 psi on a Parr shaker at about 50° C. for about 7 h. Thecatalyst was filtered off using a pad of Celite® and the filtrate wasconcd under reduced pressure. The material was purified by chiralchromatography (Table 2, method 34). The collected fractions werecombined, concd under reduced pressure and chased with EtOH (20 mL). Theresulting solid was dried in a heated vacuum oven at about 60° C. toyield(cis)-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclohexanamine(0.353 g, 60%) as a white solid: LC/MS (Table 1, Method a) R_(t)=0.85min; MS m/z 256 (M+H)⁺.

Example #404-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-8-yl)pyridin-2(1H)-one

Hydrochloric acid (4 M in 1,4-dioxane, 0.300 mL, 1.20 mmol) was added toa slurry of8-(2-methoxypyridin-4-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine(0.016 g, 0.060 mmol, (prepared using D from Preparation #BBBBB.1 andNaOH, GGG.1 with NBS, K.1 with TsCl and NaH, CCCCC with2-methoxy-4-(tributylstannyl)pyridine [Synthonix],tetrakis(triphenylphosphinepalladium(0), LiCl, CsF, and CuI, D withNaOH) in EtOH (0.500 mL) and water (0.050 mL). The reaction vessel wassealed and the mixture was warmed to about 80° C. After about 15 h, themixture was warmed to about 90° C. After about 65 h, the solution wasallowed to cool to ambient temperature. The volatiles were removed underreduced pressure to afford4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-8-yl)pyridin-2(1H)-one(0.0153 g, 94%): LC/MS (Table 1, Method a) R_(t)=0.73 min; MS m/z 253(M+H)⁺.

Example #41(1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylcyclopropylcarbamate

Step A: 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine

To a solution of 3,5-dibromopyrazin-2-amine (125 g, 494 mmol), TEA(207.0 mL, 1483 mmol), and copper (I) iodide (0.941 g, 4.94 mmol) in THF(1255 mL) was added PdCl₂(PPh₃)₂ (3.47 g, 4.94 mmol). The reactionmixture was cooled at about −5-0° C. and a solution of(trimethylsilyl)acetylene (65.0 mL, 470 mmol) in THF (157 mL) was addeddropwise over about 15 min. The reaction mixture was stirred at about−5-0° C. for about 1.5 h and then allowed to warm to rt overnight. Thereaction mixture was then filtered through a Celite® pad and washed withTHF until no further product eluted. The filtrate was concd underreduced pressure to give a brown-orange solid. The solid was trituratedand sonicated with warm petroleum ether (b.p. 30-60° C., 400 mL), cooledto rt, collected, washed with petroleum ether (b.p. 30-60° C.; 2×60 mL),and dried to give 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine(124 g, 93%, 93% purity) as a brown solid: LC/MS (Table 1, Method b)R_(t)=2.51 min; MS m/z: 270, 272 (M+H)⁺.

Step B: 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine

To a solution of 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine(3.00 g, 11.1 mmol) in DMF (60 mL) at about 0° C. was added NaH (60%dispersion in mineral oil, 0.577 g, 14 4 mmol) in three portions. Afterabout 15 min, p-toluenesulfonyl chloride (2.75 g, 14 4 mmol) was addedand the reaction was allowed to warm slowly to ambient temperature.After about 16 h, the reaction mixture was poured onto ice-cold water(120 mL) and the precipitate was collected by vacuum filtration. Thecrude solid was dissolved in DCM (15 mL) and purified by silica gelchromatography eluting with DCM to give2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (2.16 g, 52%): LC/MS (Table 1,Method c) R_(t)=1.58 min; MS m/z: 352, 354 (M+H)⁺.

Step C: tert-butyl2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate andtert-butyl 1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate

To a flask was added Pd₂(dba)₃ (3.90 g, 4.26 mmol),di-tert-butyl-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphane (3.62 g,8.52 mmol), and 1,4-dioxane (453 mL). The catalyst-ligand mixture wasdegassed via vacuum/nitrogen purge (3 times) and heated at about 80° C.for about 10 min. Then 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (30.0g, 85 mmol), tert-butyl hydrazinecarboxylate (16.9 g, 128 mmol), andNaOt-Bu (12.28 g, 128 mmol) were added. After an additionalvacuum/nitrogen purge, the reaction was heated at about 80° C. Afterabout 50 min, the reaction mixture was cooled to ambient temperature andfiltered through a pad of silica gel (6 cm in height×6 cm in diameter),topped with Celite® (1 cm in height×6 cm in diameter), while washingwith EtOAc (3×150 mL). Water (300 mL) was added to the filtrate and theorganic layer was separated. The aqueous layer was extracted withadditional EtOAc (3×200 mL). The combined organic extracts were washedwith saturated aqueous NH₄Cl, saturated aqueous NaHCO₃, and brine (400mL each), dried over anhydrous MgSO₄, filtered, and concd under reducedpressure to give a dark brown oil (45 g). The brown oil was dissolved inDCM (250 mL), silica gel (200 g) was added, and the mixture was concdunder reduced pressure. The resulting silica mixture was purified usingsilica gel chromatography eluting with a gradient of 25-65% EtOAc inheptane to give a mixture of tert-butyl2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate [majorregioisomer] and tert-butyl1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate [minorregioisomer] (18.8 g, 50%): LC/MS (Table 1, Method c) R_(t)=1.47 min; MSm/z: 404 (M+H)⁺.

Step D: 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine

To a mixture of tert-butyl2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate andtert-butyl 1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate(49.2 g, 122 mmol) in 1,4-dioxane (290 mL) was added HCl (4 M in1,4-dioxane, 226 mL, 902 mmol). The reaction was heated at about 60° C.for about 2.5 h and then cooled to about 15-20° C. The solid wascollected by vacuum filtration, washed with EtOAc (3×50 mL), and thentriturated with Et₂O (60 mL), collected by vacuum filtration and driedto a constant weight under vacuum to yield 35.6 g of solid. The solidwas stirred with a mixture of saturated aqueous NaHCO₃ and EtOAc (1:1,400 mL). After about 1 h, the solid was collected by vacuum filtration,washed with ice cold water (3×30 mL) and EtOAc (3×30 mL), and dried in avacuum oven to a constant weight to afford2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine as a tan solid (21.2 g,57%): LC/MS (Table 1, Method a) R_(t)=1.88 min; MS m/z: 304 (M+H)⁺.

Step E: sodium4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-dienolate

A round bottom flask was charged with THF (1.5 L) followed by theportionwise addition of NaH (60% dispersion in mineral oil, 70.0 g, 1.75mol). Additional THF (500 mL) was added and the resulting mixture wascooled to about −10° C. and ethyl propionylacetate (250 mL, 1.80 mol)was added dropwise over about 1 h in order to keep the internaltemperature below about 10° C. The resulting mixture was stirred atambient temperature for about 0.5 h to give a clear yellow solution, andmethyl 4-chloroacetoacetate (100 mL, 0.88 mol) was added dropwise overabout 5 min. The resulting mixture was heated at about 50° C. for about19 h to give a reddish orange suspension. The reaction mixture wascooled to ambient temperature, concd under reduced pressure and theresulting liquid was transferred to a beaker and diluted with water (350mL). The mixture was stirred in an ice bath for about 2 h. The solid wascollected by vacuum filtration and the filter cake was rinsed with water(150 mL) and dried under vacuum for about 1 h. The solid was suspendedin Et₂O (1.5 L), filtered, washed with Et₂O (1.5 L), and dried undervacuum. The resulting solid was azeotroped with toluene (1 L) to give asolid that was re-suspended in Et₂O (1 L) and collected by vacuumfiltration. The filter cake was washed with Et₂O (500 mL) and driedunder vacuum to give sodium4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-dienolate(204.2 g, 89%) as beige solid: ¹H NMR (DMSO-d₆) δ 3.94 (q, J=7.1 Hz,2H), 3.46 (s, 3H), 3.04 (q, J=7.2 Hz, 2H), 2.66 (s, 2H), 1.13 (t, J=7.1Hz, 3H), 0.99 (t, J=7.3 Hz, 3H).

Step F: ethyl 2-ethyl-4-oxocyclopent-2-enecarboxylate

A 5 L round bottom flask was charged with sodium4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-dienolate(316 g, 1205 mmol), KCl (126 g, 1687 mmol, JT-Baker), AcOH (241 mL, 4218mmol, JT-Baker), toluene (1850 mL) and water (130 mL). The reaction washeated at reflux for about 6 h then cooled to ambient temperature andadded dropwise to NaHCO₃ (8% aqueous, 3.5 L). The resulting biphasicmixture was extracted with MTBE (2×1.5 L). The combined organic layerswere washed with brine (1 L), dried over anhydrous MgSO₄ and concd underreduced pressure to give 191 g of crude material that was purified byvacuum distillation (97-99° C., 0.600 mm Hg) to give ethyl2-ethyl-4-oxocyclopent-2-enecarboxylate (160 g, 69%): ¹H NMR (CDCl₃) δ6.04 (m, 1H), 4.26-4.15 (m, 2H), 3.76-3.69 (m, 1H), 2.75-2.57 (m, 2H),2.56-2.44 (m, 2H), 1.32-1.26 (m, 3H), 1.23-1.18 (m, 3H).

Step G: ethyl 2-ethyl-4-hydroxycyclopentanecarboxylate

A mixture of copper (I) chloride (0.136 g, 1.37 mmol),(S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.854 g, 1.37mmol), and NaOt-Bu (0.132 g, 1.37 mmol) in toluene (50 mL) was stirredat ambient temperature for about 15 min then cooled to about 5° C. andpolymethylhydrosiloxane (12 mL, 55 mmol) was added. The reaction mixturewas stirred for about 40 min at about 5° C. then cooled to about −12° C.A solution of ethyl 2-ethyl-4-oxocyclopent-2-enecarboxylate (5.00 g,27.4 mmol) and t-BuOH (14 mL, 148 mmol) in toluene (50 mL) was added inone portion and the reaction mixture was stirred for about 16 h at about−12° C. The reaction mixture was quenched by the addition of MeOH (50mL). The solvents were removed under reduced pressure. The residue wasdissolved in MeOH (35 mL) and filtered through a pad of Celite®. Thefiltrate was concd under reduced pressure and the residue was trituratedwith EtOAc (100 mL) and filtered. The filtrate was concd under reducedpressure and the residue was purified using silica gel chromatography(280 g) eluting with a gradient of 0-10% EtOAc in heptane to give ascalemic mixture enriched with (1S,2R,4S)-ethyl2-ethyl-4-hydroxycyclopentanecarboxylate (1.11 g, 22%): ¹H NMR (CDCl₃) δ4.30 (m, 1H), 4.24-4.08 (m, 2H), 2.88 (td, J=2.1, 7.1 Hz, 1H), 2.40 (dt,J=7.8, 14.0 Hz, 1H), 2.08-1.91 (m, 3H), 1.52-1.31 (m, 3H), 1.29 (t,J=7.1 Hz, 3H), 0.94 (t, J=7.4 Hz, 3H).

Step H: 3-(ethoxycarbonyl)-4-ethylcyclopentyl 4-nitrobenzoate

To triphenylphosphine (34.9 g, 133 mmol) in THF (150 mL) at about 0° C.was added a solution of DIAD (26.2 mL, 133 mmol) in THF (20 mL) throughan additional funnel. After about 30 min, a solution of 4-nitrobenzoicacid (22.26 g, 133 mmol) in THF (150 mL) was added followed by asolution of a scalemic mixture enriched with (1S,2R,4S)-ethyl2-ethyl-4-hydroxycyclopentanecarboxylate (16.54 g, 89 mmol) in THF (20mL) and triethylamine (55.7 mL, 400 mmol). After about 1 h, the icewater bath was removed and the reaction mixture was stirred at ambienttemperature for about 16 h. The reaction mixture was diluted withheptane (800 mL), washed with water (200 mL), saturated aqueous NaHCO₃(150 mL) and brine (150 mL), dried over anhydrous MgSO₄, filtered, andconcd under reduced pressure. After about 300 mL of solvent was removed,the solid was filtered off and washed with heptane (25 mL). The filtratewas concentrated under reduced pressure and the residue was purifiedusing silica gel chromatography eluting with 10-40% EtOAc in heptane togive a scalemic mixture enriched with(1R,3S,4R)-3-(ethoxycarbonyl)-4-ethylcyclopentyl 4-nitrobenzoate (26.77g, 90%): LC/MS (Table 1, Method b) R_(t)=2.84 min; MS m/z: 394 (M−H)⁻.

Step I: ethyl 2-ethyl-4-hydroxycyclopentanecarboxylate

A 2 L flask was charged with freshly ground sodium hydroxide (9.55 g,239 mmol). Ethanol (500 mL) was added and the mixture was stirred untilall solid went into solution. A solution of a scalemic mixture enrichedin (1R,3S,4R)-3-(ethoxycarbonyl)-4-ethylcyclopentyl 4-nitrobenzoate(16.02 g, 47.8 mmol) in ethanol (120 mL) was added through an additionalfunnel. The reaction mixture was stirred at ambient temperatureovernight. The solid was filtered off while washing with DCM (100 mL).Saturated aqueous NaHCO₃ (800 mL) was added to the filtrate and mixturewas stirred for about 30 min. The solid formed was filtered off whilewashing with DCM (500 mL). The filtrate was washed with saturatedaqueous NaHCO₃ (2×200 mL) and brine (300 mL). The organic layer wasdried over anhydrous MgSO₄, filtered and concd under reduced pressure.The residue was purified using silica gel chromatography eluting with0-60% EtOAc in DCM to give a scalemic mixture enriched in(1S,2R,4R)-ethyl 2-ethyl-4-hydroxycyclopentanecarboxylate (5.49 g, 62%)as a colorless oil: ¹H NMR (400 MHz, CDCl₃) δ 4.53 (m, 1H), 4.11 (m,2H), 3.09 (m 1H), 2.40 (m, 1H), 2.28 (m, 1H), 1.80 (m, 1H), 1.68 (m,1H), 1.44 (m, 2H), 1.26 (t, 3H), 1.18 (m, 1H), 0.92 (t, 3H).

Step J: 2-ethyl-4-hydroxycyclopentanecarboxylic acid

Aqueous sodium hydroxide (1N, 32.4 mL, 32 4 mmol) was added to ascalemic mixture enriched in (1S,2R,4R)-ethyl2-ethyl-4-hydroxycyclopentanecarboxylate (3.02 g, 16.21 mmol) and thereaction mixture was stirred at ambient temperature overnight. Ether (15mL) was added and the layers were separated. The aqueous layer wascooled to about 0° C. Aqueous HCl (5N) was slowly added to bring pH toabout 1. The aqueous suspension was extracted with EtOAc (4×40 mL). Thecombined organic layers were washed with brine (50 mL), dried overanhydrous MgSO₄, filtered and concd under reduced pressure to give ascalemic mixture enriched in(1S,2R,4R)-2-ethyl-4-hydroxycyclopentanecarboxylic acid (2.56 g, 100%):LC/MS (Table 1, Method b) R_(t)=1.36 min; MS m/z: 157 (M−H)⁻.

Step K: 4-(tert-butyldimethylsilyloxy)-2-ethylcyclopentanecarboxylicacid

To a scalemic mixture enriched in(1S,2R,4R)-2-ethyl-4-hydroxycyclopentanecarboxylic acid (2.56 g, 16.21mmol) in DMF (10.81 mL) was added TBDMSCl (2.93 g, 19.45 mmol) andimidazole (2.76 g, 40.5 mmol). The reaction mixture was stirred atambient temperature for about 2 days then extracted with pentane (3×25mL). The combined pentane layers were washed with water (25 mL) andbrine (25 mL), dried over anhydrous MgSO₄, filtered and concd underreduced pressure. The residue was purified using silica gelchromatography eluting with 20-100% EtOAc in heptane give a scalemicmixture enriched in(1S,2R,4R)-4-(tert-butyldimethylsilyloxy)-2-ethylcyclopentanecarboxylicacid (1.13 g, 26%): LC/MS (Table 1, Method b) R_(t)=3.03 min; MS m/z:273 (M+H)⁺.

Step L:4-(tert-butyldimethylsilyloxy)-2-ethyl-N-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)cyclopentanecarbohydrazide

To a scalemic mixture enriched in(1S,2R,4R)-4-(tert-butyldimethylsilyloxy)-2-ethylcyclopentanecarboxylicacid (1.62 g, 5.96 mmol) in DCM (60 mL) was added2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (Example #1, Step D, 1.86g, 6.13 mmol), HATU (2.38 g, 6.26 mmol) and TEA (3.32 mL, 23.8 mmol).The reaction mixture was stirred at ambient temperature for about 1 h.The reaction mixture was diluted with DCM (200 mL), washed with water(50 mL) and brine (50 mL), dried over anhydrous MgSO₄, filtered, andconcd under reduced pressure. The residue was purified using silica gelchromatography eluting with 0-30% EtOAc in DCM to give a scalemicmixture enriched in(1S,2R,4R)-4-(tert-butyldimethylsilyloxy)-2-ethyl-N′-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)cyclopentanecarbohydrazide(2.64 g, 79%) as a brown solid: LC/MS (Table 1, Method b) R_(t)=3.20min; MS m/z: 558 (M+H)⁺.

Step M:4-(tert-butyldimethylsilyloxy)-2-ethylcyclopentyl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine

To a scalemic mixture enriched in(1S,2R,4R)-4-(tert-butyldimethylsilyloxy)-2-ethyl-Y-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)cyclopentanecarbohydrazide(2.6 g, 4.66 mmol) in 1,4-dioxane (46.6 mL) was addeddiisopropylethylamine (3.26 mL, 18.65 mmol) followed by dropwiseaddition of thionyl chloride (0.680 mL, 9.32 mmol). The reaction mixturewas stirred at ambient temperature for about 1 h and then heated atabout 70° C. for about 1 h. The reaction mixture was cooled to ambienttemperature and EtOAc (300 mL) was added. The mixture was washed withwater (80 mL) and brine (80 mL), dried over anhydrous MgSO₄, filtered,and concd under reduced pressure. The residue was purified by silica gelchromatography eluting with 0-50% EtOAc in DCM to give a scalemicmixture enriched in1-((1S,2R,4R)-4-(tert-butyldimethylsilyloxy)-2-ethylcyclopentyl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine(1.56 g, 62%): LC/MS (Table 1, Method b) R_(t)=3.36 min; MS m/z: 540(M+H)⁺.

Step N:3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanol

A scalemic mixture enriched in1-((1S,2R,4R)-4-(tert-butyldimethylsilyloxy)-2-ethylcyclopentyl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine(1.55 g, 2.87 mmol) was suspended in ethanol (30 mL). Concentrated HCl(0.3 mL, 3.65 mmol) was added dropwise. After about 1 h., the suspensionwas sonicated until all solid went into solution. EtOAc (250 mL) wasadded and the organics were washed with saturated aqueous NaHCO₃ (2×30mL) and brine (30 mL), dried over anhydrous MgSO₄, filtered, and concdunder reduce pressure. The residue was purified using silica gelchromatography eluting with 30-80% EtOAc in DCM to give a scalemicmixture enriched in(1R,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanol(1.09 g, 90%): LC/MS (Table 1, Method b) R_(t)=1.99 min; MS m/z: 426(M+H)⁺.

Step O:3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl4-nitrophenyl carbonate

To a scalemic mixture enriched in(1R,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanol(1.20 g, 2.82 mmol) in pyridine (10 mL) was added DMAP (0.103 g, 0.846mmol) and 4-nitrophenyl carbonochloridate (0.853 g, 4.23 mmol). Theresulting mixture was stirred at ambient temperature for about 1 h. Thereaction mixture was purified using silica gel chromatography elutingwith 0-30% EtOAc in DCM to give a scalemic mixture enriched in(1R,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl4-nitrophenyl carbonate (0.72 g. 43%): LC/MS (Table 1, Method b)R_(t)=2.64 min; MS m/z: 591 (M+H)⁺.

Step P:(1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylcyclopropylcarbamate

To a scalemic mixture enriched in(1R,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl4-nitrophenyl carbonate (0.211 g, 0.357 mmol) in 1,4-dioxane (1.5 mL)was added cyclopropanamine (0.102 g, 1.786 mmol). After about 1 h,aqueous NaOH (1N, 1.5 mL, 1.5 mmol) was added and the reaction mixturewas heated at about 60° C. for about 30 min then cooled to ambienttemperature. The reaction mixture was extracted with DCM (3×5 mL). Thecombined organic solvents were concd under reduced pressure. The residuewas purified using silica gel chromatography eluting with 0-100%EtOAc:MeOH (9:1) in EtOAc to give(1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylcyclopropylcarbamate (0.0847 g, 67%): LC/MS (Table 1, Method b)R_(t)=1.73 min; MS m/z: 355 (M+H)⁺.

Example #42(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylcyclobutylcarbamate

Step A: 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine

To a solution of 3,5-dibromopyrazin-2-amine (125 g, 494 mmol), TEA(207.0 mL, 1483 mmol), and copper (I) iodide (0.941 g, 4.94 mmol) in THF(1255 mL) was added PdCl₂(PPh₃)₂ (3.47 g, 4.94 mmol). The reactionmixture was cooled at about −5-0° C. and a solution of(trimethylsilyl)acetylene (65.0 mL, 470 mmol) in THF (157 mL) was addeddropwise over about 15 min. The reaction mixture was stirred at about−5-0° C. for about 1.5 h and then allowed to warm to rt overnight. Thereaction mixture was then filtered through a Celite® pad and washed withTHF until no further product eluted. The filtrate was concd underreduced pressure to give a brown-orange solid. The solid was trituratedand sonicated with warm petroleum ether (b.p. 30-60° C., 400 mL), cooledto rt, collected, washed with petroleum ether (b.p. 30-60° C.; 2×60 mL),and dried to give 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine(124 g, 93%, 93% purity) as a brown solid: LC/MS (Table 1, Method b)R_(t)=2.51 min; MS m/z: 270, 272 (M+H)⁺.

Step B: 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine

To a solution of 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine(3.00 g, 11.1 mmol) in DMF (60 mL) at about 0° C. was added NaH (60%dispersion in mineral oil, 0.577 g, 14 4 mmol) in three portions. Afterabout 15 min, p-toluenesulfonyl chloride (2.75 g, 14 4 mmol) was addedand the reaction was allowed to warm slowly to ambient temperature.After about 16 h, the reaction mixture was poured onto ice-cold water(120 mL) and the precipitate was collected by vacuum filtration. Thecrude solid was dissolved in DCM (15 mL) and purified by silica gelchromatography eluting with DCM to give2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (2.16 g, 52%): LC/MS (Table 1,Method c) R_(t)=1.58 min; MS m/z: 352, 354 (M+H)⁺.

Step C: tert-butyl2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate andtert-butyl 1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate

To a flask was added Pd₂(dba)₃ (3.90 g, 4.26 mmol),di-tert-butyl-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphane (3.62 g,8.52 mmol), and 1,4-dioxane (453 mL). The catalyst-ligand mixture wasdegassed via vacuum/nitrogen purge (3 times) and heated at about 80° C.for about 10 min. Then 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (30.0g, 85 mmol), tert-butyl hydrazinecarboxylate (16.9 g, 128 mmol), andNaOt-Bu (12.28 g, 128 mmol) were added. After an additionalvacuum/nitrogen purge, the reaction was heated at about 80° C. Afterabout 50 min, the reaction mixture was cooled to ambient temperature andfiltered through a pad of silica gel (6 cm in height×6 cm in diameter),topped with Celite® (1 cm in height×6 cm in diameter), while washingwith EtOAc (3×150 mL). Water (300 mL) was added to the filtrate and theorganic layer was separated. The aqueous layer was extracted withadditional EtOAc (3×200 mL). The combined organic extracts were washedwith saturated aqueous NH₄Cl, saturated aqueous NaHCO₃, and brine (400mL each), dried over anhydrous MgSO₄, filtered, and concd under reducedpressure to give a dark brown oil (45 g). The brown oil was dissolved inDCM (250 mL), silica gel (200 g) was added, and the mixture was concdunder reduced pressure. The resulting silica mixture was purified usingsilica gel chromatography eluting with a gradient of 25-65% EtOAc inheptane to give a mixture of tert-butyl2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate [majorregioisomer] and tert-butyl1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate [minorregioisomer] (18.8 g, 50%): LC/MS (Table 1, Method c) R_(t)=1.47 min; MSm/z: 404 (M+H)⁺.

Step D: 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine

To a mixture of tert-butyl2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate andtert-butyl 1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate(49.2 g, 122 mmol) in 1,4-dioxane (290 mL) was added HCl (4 M in1,4-dioxane, 226 mL, 902 mmol). The reaction was heated at about 60° C.for about 2.5 h and then cooled to about 15-20° C. The solid wascollected by vacuum filtration, washed with EtOAc (3×50 mL), and thentriturated with Et₂O (60 mL), collected by vacuum filtration and driedto a constant weight under vacuum to yield 35.6 g of solid. The solidwas stirred with a mixture of saturated aqueous NaHCO₃ and EtOAc (1:1,400 mL). After about 1 h, the solid was collected by vacuum filtration,washed with ice cold water (3×30 mL) and EtOAc (3×30 mL), and dried in avacuum oven to a constant weight to afford2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine as a tan solid (21.2 g,57%): LC/MS (Table 1, Method a) R_(t)=1.88 min; MS m/z: 304 (M+H)⁺.

Step E: sodium4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-dienolate

A round bottom flask was charged with THF (1.5 L) followed by theportionwise addition of NaH (60% dispersion in mineral oil, 70.0 g, 1.75mol). Additional THF (500 mL) was added and the resulting mixture wascooled to about −10° C. and ethyl propionylacetate (250 mL, 1.80 mol)was added dropwise over about 1 h in order to keep the internaltemperature below about 10° C. The resulting mixture was stirred atambient temperature for about 0.5 h to give a clear yellow solution, andmethyl 4-chloroacetoacetate (100 mL, 0.88 mol) was added dropwise overabout 5 min. The resulting mixture was heated at about 50° C. for about19 h to give a reddish orange suspension. The reaction mixture wascooled to ambient temperature, concd under reduced pressure and theresulting liquid was transferred to a beaker and diluted with water (350mL). The mixture was stirred in an ice bath for about 2 h. The solid wascollected by vacuum filtration and the filter cake was rinsed with water(150 mL) and dried under vacuum for about 1 h. The solid was suspendedin Et₂O (1.5 L), filtered, washed with Et₂O (1.5 L), and dried undervacuum. The resulting solid was azeotroped with toluene (1 L) to give asolid that was re-suspended in Et₂O (1 L) and collected by vacuumfiltration. The filter cake was washed with Et₂O (500 mL) and driedunder vacuum to give sodium4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-dienolate(204.2 g, 89%) as beige solid: ¹H NMR (DMSO-d₆) δ 3.94 (q, J=7.1 Hz,2H), 3.46 (s, 3H), 3.04 (q, J=7.2 Hz, 2H), 2.66 (s, 2H), 1.13 (t, J=7.1Hz, 3H), 0.99 (t, J=7.3 Hz, 3H).

Step F: ethyl 2-ethyl-4-oxocyclopent-2-enecarboxylate

A 5 L round bottom flask was charged with sodium4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-dienolate(316 g, 1205 mmol), KCl (126 g, 1687 mmol, JT-Baker), AcOH (241 mL, 4218mmol, JT-Baker), toluene (1850 mL) and water (130 mL). The reaction washeated at reflux for about 6 h then cooled to ambient temperature andadded dropwise to NaHCO₃ (8% aqueous, 3.5 L). The resulting biphasicmixture was extracted with MTBE (2×1.5 L). The combined organic layerswere washed with brine (1 L), dried over anhydrous MgSO₄ and concd underreduced pressure to give 191 g of crude material that was purified byvacuum distillation (97-99° C., 0.600 mm Hg) to give ethyl2-ethyl-4-oxocyclopent-2-enecarboxylate (160 g, 69%): ¹H NMR (CDCl₃) δ6.04 (m, 1H), 4.26-4.15 (m, 2H), 3.76-3.69 (m, 1H), 2.75-2.57 (m, 2H),2.56-2.44 (m, 2H), 1.32-1.26 (m, 3H), 1.23-1.18 (m, 3H).

Step G: ethyl 2-ethyl-4-hydroxycyclopentanecarboxylate

A mixture of copper (I) chloride (0.136 g, 1.37 mmol),(S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.854 g, 1.37mmol), and NaOt-Bu (0.132 g, 1.37 mmol) in toluene (50 mL) was stirredat ambient temperature for about 15 min then cooled to about 5° C. andpolymethylhydrosiloxane (12 mL, 55 mmol) was added. The reaction mixturewas stirred for about 40 min at about 5° C. then cooled to about −12° C.A solution of ethyl 2-ethyl-4-oxocyclopent-2-enecarboxylate (5.00 g,27.4 mmol) and t-BuOH (14 mL, 148 mmol) in toluene (50 mL) was added inone portion and the reaction mixture was stirred for about 16 h at about−12° C. The reaction mixture was quenched by the addition of MeOH (50mL). The solvents were removed under reduced pressure. The residue wasdissolved in MeOH (35 mL) and filtered through a pad of Celite®. Thefiltrate was concd under reduced pressure and the residue was trituratedwith EtOAc (100 mL) and filtered. The filtrate was concd under reducedpressure and the residue was purified using silica gel chromatographyeluting with a gradient of 0-10% EtOAc in heptane to give a scalemicmixture enriched with (1S,2R,4S)-ethyl2-ethyl-4-hydroxycyclopentanecarboxylate (1.11 g, 22%): ¹H NMR (CDCl₃) δ4.30 (m, 1H), 4.24-4.08 (m, 2H), 2.88 (td, J=2.1, 7.1 Hz, 1H), 2.40 (dt,J=7.8, 14.0 Hz, 1H), 2.08-1.91 (m, 3H), 1.52-1.31 (m, 3H), 1.29 (t,J=7.1 Hz, 3H), 0.94 (t, J=7.4 Hz, 3H).

Step H: 2-ethyl-4-hydroxycyclopentanecarboxylic acid

Aqueous NaOH (1 N, 12 mL, 12 mmol) was added to a scalemic mixtureenriched in (1S,2R,4S)-ethyl 2-ethyl-4-hydroxycyclopentanecarboxylate(1.11 g, 5.96 mmol). The reaction mixture was stirred at ambienttemperature for about 3 days and then extracted with Et₂O (3×25 mL). TheEt₂O extracts were discarded and the aqueous portion was cooled to about0° C. Aqueous HCl (5 N) was slowly added to bring the pH to about 2. Theresulting aqueous suspension was extracted with EtOAc (3×40 mL). Thecombined organic layers were washed with brine (2×80 mL), dried overanhydrous MgSO₄, filtered, and concd under reduced pressure to give ascalemic mixture enriched in(1S,2R,4S)-2-ethyl-4-hydroxycyclopentanecarboxylic acid (0.943 g, 100%)as clear oil: ¹H NMR (CDCl₃) δ 4.36 (tdd, J=2.6, 4.9, 7.4, 1H), 2.95(td, J=2.4, 7.3, 1H), 2.41 (dt, J=7.7, 14.1, 1H), 2.16 1.94 (m, 3H),1.65 1.49 (m, 1H), 1.49 1.32 (m, 2H), 0.96 (q, J=7.4, 3H).

Step I: 5-ethyl-2-oxabicyclo[2.2.1]heptan-3-one

To a scalemic mixture enriched in(1S,2R,4S)-2-ethyl-4-hydroxycyclopentanecarboxylic acid (0.943 g, 5.96mmol) in DCM (60 mL) was added TEA (2.5 mL, 18 mmol) and BOP-Cl (1.821g, 7.15 mmol). The reaction mixture was stirred at ambient temperaturefor about 2 h then poured into Et₂O (350 mL). The solid was removed byfiltration while washing with Et₂O (50 mL). The filtrate was concd underreduced pressure to give a yellow oil which was dissolved in DCM (5 mL)and Et₂O was added to give a solid. The supernatant was decanted and thesolid was washed with additional Et₂O. The combined organic extractswere concd under reduced pressure to give a scalemic mixture enriched incrude (1S,4S,5R)-5-ethyl-2-oxabicyclo[2.2.1]heptan-3-one containingabout 15 mol % TEA (0.912 g, 99%): ¹H NMR (CDCl₃) δ 4.85 (s, 1H), 2.88(s, 1H), 2.19 (m, 2H), 2.08 (m, 1H), 1.69 (m, 1H), 1.41 (m, 3H), 0.97(t, J=5.4, 3H).

Step J:2-ethyl-4-hydroxy-N′-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)cyclopentanecarbohydrazide

To a scalemic mixture enriched in(1S,4S,5R)-5-ethyl-2-oxabicyclo[2.2.1]heptan-3-one (0.835 g, 5.96 mmol)in 1,4-dioxane (12 mL) was added2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (step D, 1.810 g, 5.96mmol). The reaction mixture was heated at about 80° C. for about 16 hthen cooled to ambient temperature. 1,4-Dioxane (25 mL) andtrimethylaluminum (2 N in toluene, 9 mL, 18 mmol) were addedsequentially. The reaction mixture was stirred at ambient temperaturefor about 30 min then aqueous HCl (1 N, 50 mL) was added dropwise andthe reaction mixture was stirred for about 30 min. The layers wereseparated and the aqueous layer was extracted with EtOAc (2×100 mL). Thecombined organic extracts were washed with water (10 mL), saturatedaqueous NaHCO₃ (15 mL), brine (15 mL) and dried over anhydrous MgSO₄,filtered, and concd under reduced pressure. The residue was purifiedusing silica gel chromatography eluting with 100% EtOAc to give ascalemic mixture enriched in(1S,2R,4S)-2-ethyl-4-hydroxy-N′-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)cyclopentanecarbo-hydrazide(1.887 g, 71%): LC/MS (Table 1, Method b) R_(t)=2.05 min; MS m/z: 444(M+H)⁺.

Step K:4-(tert-butyldimethylsilyloxy)-2-ethyl-N-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)cyclopentanecarbohydrazide

To a scalemic mixture enriched in(1S,2R,4S)-2-ethyl-4-hydroxy-N-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)cyclopentanecarbo-hydrazide(9.06 g, 20.43 mmol) in DMF (40.9 mL) was added TBDMSCl (3.69 g, 24.51mmol) and imidazole (3.48 g, 51.1 mmol). The reaction mixture wasstirred at ambient temperature for about 4 h. The solvent was removedunder reduced pressure. The residue was diluted with EtOAc (200 mL),filtered, and washed with EtOAc (20 mL). The filtrate was concd underreduced pressure. The residue was purified using silica gelchromatography eluting with 0-50% EtOAc in DCM to give a scalemicmixture enriched in(1S,2R,4S)-4-(tert-butyldimethylsilyloxy)-2-ethyl-N′-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)cyclopentanecarbohydrazide(11.37 g, 100%) as an orange solid: LC/MS (Table 1, Method b) R_(t)=3.14min; MS m/z: 558 (M+H)⁺.

Step L:4-(tert-butyldimethylsilyloxy)-2-ethylcyclopentyl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine

To a scalemic mixture enriched in(1S,2R,4S)-4-(tert-butyldimethylsilyloxy)-2-ethyl-N-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)cyclopentanecarbohydrazide(11.37 g, 20.38 mmol) in 1,4-dioxane (204 mL) was added DIEA (14.24 mL,82 mmol) followed by thionyl chloride (2.98 mL, 40.8 mmol) dropwise overabout 25 min. The reaction mixture was stirred at ambient temperaturefor about 1 h and heated at about 70° C. for about 1 h. The reactionmixture was cooled to ambient temperature and EtOAc (600 mL) was added.The organic mixture was washed with water (80 mL) and brine (80 mL),dried over anhydrous MgSO₄, filtered and concd under reduced pressure.The residue was purified using silica gel chromatography eluting with0-50% EtOAc in DCM to give a scalemic mixture enriched in1-((1S,2R,4S)-4-(tert-butyldimethylsilyloxy)-2-ethylcyclopentyl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine(9.58 g, 87%). LC/MS (Table 1, Method b) R_(t)=3.24 min; MS m/z: 540(M+H)⁺.

Step M:3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanol

A scalemic mixture enriched in1-((1S,2R,4S)-4-(tert-butyldimethylsilyloxy)-2-ethylcyclopentyl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine(9.58 g, 17.8 mmol) was dissolved in ethanol (177 mL). Concd HCl (1.75mL, 21.3 mmol) was added dropwise. After about 1 h, EtOAc (700 mL) wasadded. The organic mixture was washed with saturated aqueous NaHCO₃(2×120 mL), brine (120 mL), dried over anhydrous MgSO₄, filtered andconcd under reduced pressure. The residue was purified using silica gelchromatography eluting with 30-100% EtOAc in DCM to give a scalemicmixture enriched in(1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanol(6.73 g, 89%): LC/MS (Table 1, Method b) R_(t)=2.11 min; MS m/z: 426(M+H)⁺.

Step N:3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl4-nitrophenyl carbonate

To a scalemic mixture enriched in(1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanol(6.11 g, 14 4 mmol) in pyridine (100 mL) was added DMAP (1.93 g, 15.8mmol) and 4-nitrophenyl carbonochloridate (4.34 g, 21.5 mmol). Theresulting mixture was stirred at ambient temperature for about 3.5 h andheated at about 33° C. for about 1 h. The solid was filtered off andwashed with EtOAc (30 mL). The filtrated was concd under reducedpressure. The residue was purified using silica gel chromatographyeluting with 0-30% EtOAc in heptane to give a scalemic mixture enrichedin(1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl4-nitrophenyl carbonate (6.63, 78%). LC/MS (Table 1, Method b)R_(t)=2.65 min; MS m/z: 591 (M+H)⁺.

Step O:(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylcyclobutylcarbamate

A solution of a scalemic mixture enriched in(1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl4-nitrophenyl carbonate (0.150 g, 0.254 mmol) in 1,4-dioxane (1 mL) wasadded to a solution of cyclobutanamine (0.090 g, 1.27 mmol) in1,4-dioxane (0.2 mL). After about 1 h, aqueous NaOH (1 N, 1.5 mL, 1.50mmol) was added and the reaction mixture was heated at about 60° C. forabout 2 h before cooling to rt. The organic solvent was removed underreduced pressure. The resulting aqueous layer mixture was acidified withAcOH to pH about 5 and extracted with DCM (3×5 mL). The combined organicextracts were concentrated under reduced pressure. The residue waspurified by preparative HPLC (Table 1 method d) to give(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylcyclobutylcarbamate (0.0468 g, 50%): LC/MS (Table 1, Method c)R_(t)=1.17 min; MS m/z: 369 (M+H)⁺.

TABLE 4 Jak3 enzyme data for selected compounds JAK3 enzyme Example#IC₅₀ A.1.105 B A.1.65 B A.1.78 A AA.1.10 B AA.1.100 C AA.1.101 AAA.1.102 C AA.1.103 A AA.1.104 A AA.1.106 C AA.1.107 A AA.1.11 A AA.1.12A AA.1.16 B AA.1.18 A AA.1.22 A AA.1.25 A AA.1.29 C AA.1.3 B AA.1.32 BAA.1.33 B AA.1.37 B AA.1.42 C AA.1.43 A AA.1.44 B AA.1.49 A AA.1.5 BAA.1.54 B AA.1.6 A AA.1.60 B AA.1.61 B AA.1.62 B AA.1.63 C AA.1.64 CAA.1.66 C AA.1.67 C AA.1.76 C AA.1.77 A AA.1.79 A AA.1.8 A AA.1.80 CAA.1.81 A AA.1.9 B AA.1.90 B AA.1.91 B AA.1.92 A AA.1.93 C AA.1.94 BAA.1.95 C AA.1.96 C AA.1.97 C AA.1.98 A AA.1.99 B D.1.10 B D.1.11 BD.1.12 B D.1.13 B D.1.21 B D.1.22 B D.1.24 B D.1.25 A D.1.29 B D.1.30 BD.1.31 A D.1.33 C D.1.35 A D.1.38 B D.1.39 B D.1.45 A D.1.46 A D.1.47 BD.1.49 B D.1.50 C D.1.51 C D.1.52 B D.1.54 C D.1.56 B D.1.58 B D.1.59 BD.1.60 C D.1.61 C D.1.62 C D.1.63 C D.1.64 C D.1.65 C D.1.66 C D.1.67 BD.1.69 C D.1.70 B D.1.71 C D.1.72 B D.1.73 C D.1.76 B D.1.77 B D.1.78 AD.1.79 A D.1.80 A D.1.81 A D.1.82 B D.1.83 A D.1.84 B D.2.10 C D.2.11 BD.2.13 A D.2.15 B D.2.19 B D.2.21 B D.2.22 B D.2.23 C D.2.24 A D.2.5 BD.2.6 C DD.1.1 A Example A #29 Example B #30 Example B #31 Example A #14Example A #17 Example B #18 Example B #21 Example C #22 Example A #23Example A #24 Example A #25 Example B #26 Example C #27 Example C #28Example A #3 Example B #32 Example A #4 Example B #5 Example B #6Example B #8 Example B #9 H.1.1 A H.1.10 A H.1.2 A H.1.21 A H.1.25 AH.1.29 A H.1.6 A H.3.14 B H.4.1 B I.1.1 A I.1.2 A I.2.1 A I.2.2 A I.3.1B J.1.1 A J.2.1 A J.2.10 A J.2.11 A J.2.12 A J.2.13 A J.2.14 A J.2.15 AJ.2.2 A J.2.3 A J.2.5 A J.2.6 A J.2.7 A J.2.8 A J.2.9 A J.3.1 A J.3.10 AJ.3.11 A J.3.2 A J.3.4 A J.3.6 B J.3.7 B J.3.8 B K.3.1 B K.4.1 A K.5.1 AL.1.2 A L.1.4 A LL.1.1 B LL.1.2 C LL.1.3 C LL.1.4 C Preparation B #GGG.1QQ.1.4 A UUU.1.1 A UUU.1.1 A YY.1.1 C YY.1.2 C Key: A <0.1 μM B 0.1-1 μMC >1 μM

What is claimed:
 1. A compound of Formula (I)

pharmaceutically acceptable salts, pro-drugs, biologically activemetabolites, stereoisomers and isomers thereof wherein T is N, U is N, Xis CR³ and Y is N; or T is CR⁶, U is N, X is CR³ and Y is N; or T is N,U is CR⁴, X is CR³ and Y is N; or T is CR⁶, U is CR⁴, X is CR³ and Y isN; or T is CR⁶, U is N, X is NR³ and Y is C; or T is O, U is N, X is CR³and Y is C; or T is NR⁶, U is N, X is CR³ and Y is C; or T is CR⁶, U isCR⁴, X is NR³ and Y is C; or T is S, U is N, X is CR³ and Y is C; or Tis N, U is CR⁴, X is NR³ and Y is C; or T is N, U is N, X is NR³ and Yis C; R¹, R² and R⁵ are each independently hydrogen, deuterium,—N(R^(a))(R^(b)), halogen, —OR^(a), —SR^(a), —S(O)R^(a), —S(O)₂R^(a),—NO₂, —C(O)OR^(a), —CN, —C(O)N(R^(a))(R^(b)), —N(R^(a))C(O)(R^(b)),—C(O)R^(a), —C(OH)R^(a)R^(b), —N(R^(a))S(O)₂—R^(b),—S(O)₂N(R^(a))(R^(b)), —CF₃, —OCF₃, optionally substituted (C₁-C₆)alkyl,optionally substituted (C₂-C₆)alkenyl, optionally substituted(C₂-C₆)alkynyl, optionally substituted (C₃-C₁₀)cycloalkyl, optionallysubstituted (C₁-C₁₀)heteroaryl, optionally substituted (C₁-C₁₀)heterocyclyl, or optionally substituted (C₆-C₁₀)aryl; wherein in amoiety containing —N(R^(a))(R^(b)), the nitrogen, R^(a) and R^(b) mayform a ring such that —N(R^(a))(R^(b)) represents an optionallysubstituted (C₂-C₁₀)heterocyclyl or optionally substituted(C₁-C₁₀)heteroaryl linked through a nitrogen; R³ is hydrogen, anoptionally substituted bridged (C₅-C₁₂)cycloalkyl, optionallysubstituted bridged (C₂-C₁₀)heterocyclyl, optionally substituted(C₁-C₈)alkyl, optionally substituted (C₃-C₁₀)cycloalkyl, optionallysubstituted (C₃-C₈)cycloalkenyl, optionally substituted (C₆-C₁₀)aryl,optionally substituted (C₁-C₁₀)heteroaryl, optionally substituted(C₂-C₁₀)heterocyclyl; or R³ is -A-D-E-G, wherein: A is a bond, —C(O)—,optionally substituted (C₁-C₆)alkylene, optionally substituted(C₂-C₆)alkenylene, optionally substituted (C₂-C₆)alkynylene, optionallysubstituted (C₃-C₁₂)cycloalkylene, optionally substituted(C₂-C₆)heterocyclylene, —C(O)N(R^(a))—R^(e)—, —N(R^(a))C(O)—R^(e)—,—O—R^(e)—, —N(R^(a))—R^(e)—, —S—R^(e)—, —S(O)₂—R^(e)—, —S(O)R^(e)—,—C(O—R^(a))(R^(b))—R^(e)—, —S(O)₂N(R^(a))—R^(e)—, —N(R^(a))S(O)₂—R^(e)—or —N(R^(a))C(O)N(R^(b))—R^(e)—; D is an optionally substituted(C₁-C₈)alkylene, optionally substituted bridged (C₅-C₁₂)cycloalkylene,optionally substituted (C₃-C₁₀)cycloalkylene, optionally substitutedbridged (C₅-C₁₀)cycloalkenylene, optionally substituted(C₃-C₁₀)cycloalkenylene, optionally substituted (C₆-C₁₀)arylene,optionally substituted (C₁-C₁₀)heteroarylene, optionally substitutedbridged (C₂-C₁₀)heterocyclylene or an optionally substituted(C₂-C₁₀)heterocyclylene; E is a bond, —R^(e)—, —R^(e)—C(═NCN)—R^(e)—,—R^(e)—C(O)—R^(e)—, —R^(e)—C(O)C(O)—R^(e)—, —R^(e)—C(O)O—R^(e)—,—R^(e)—C(O)C(O)N(R^(a))—R^(e)—, —R^(e)—N(R^(a))—C(O)C(O)—R^(e)—,—R^(e)—O—R^(e)—, —R^(e)—S(O)₂—R^(e)—, —R^(e)—S(O)—R^(e)—,—R^(e)—S—R^(e)—, —R^(e)—N(R^(a))—R^(e)—, ═N—R^(e)—,—R^(e)—N(R^(a))C(O)—R^(e)—, —R^(e)C(O)N(R^(a))R^(e)—,—R^(e)—OC(O)N(R^(a))—R^(e)—, —R^(e)—N(R^(a))C(O)OR^(e)—,—R^(e)—OC(O)—R^(e), —R^(e)—OC(O)—O—R^(e),—R^(e)—N(R^(a))C(O)N(R^(b))—R^(e)—, —R^(e)—N(R^(a))S(O)₂—R^(e)—,—R^(e)—S(O)₂N(R^(a))—R^(e)—, or —R^(e)—N(R^(a))S(O)₂N(R^(a))—R^(e)—; orE is

where in all cases, E is linked to either a carbon or a nitrogen atom inD; G is hydrogen, deuterium, —N(R^(a))(R^(b)), halogen, —OR^(a),—SR^(a), —S(O)R^(a), —S(O)₂R^(a), —NO₂, —C(O)OR^(a), —CN,—C(O)N(R^(a))(R^(b)), —N(R^(a))C(O)R^(b), —N(R^(a))C(O)OR^(b),—OC(O)N(R^(a)), —N(R^(a))C(O)N(R^(b))₂, —C(O—R^(a))(R^(b))₂, —C(O)R^(a),—CF₃, —OCF₃, —N(R^(a))S(O)₂R^(b), —S(O)₂N(R^(a))(R^(b)),—S(O)₂N(R^(a))C(O)R^(b), an optionally substituted —(C₁-C₆)alkyl, anoptionally substituted —(C₂-C₆)alkenyl, an optionally substituted—(C₂-C₆)alkynyl, an optionally substituted —(C₃-C₁₀)cycloalkyl, anoptionally substituted —(C₁-C₁₀)heteroaryl, an optionally substituted—(C₁-C₁₀) heterocyclyl, an optionally substituted —(C₆-C₁₀)aryl; whereinin a moiety containing —N(R^(a))(R^(b)), the nitrogen, R^(a) and R^(b)may form a ring such that —N(R^(a))(R^(b)) represents an optionallysubstituted (C₂-C₁₀)heterocyclyl or an optionally substituted (C₁-C₁₀)heteroaryl linked through a nitrogen; R⁴ and R⁶ are each independently ahydrogen, halogen, deuterium, CF₃, CHF₂, CH₂F, CH₂CF₃, C(O)OH, C(O)OCH₃,CN, an optionally substituted bridged (C₅-C₁₂)cycloalkyl group,optionally substituted bridged (C₂-C₁₀)heterocyclyl group, optionallysubstituted (C₁-C₈)alkyl, optionally substituted (C₃-C₁₀)cycloalkyl,optionally substituted (C₃-C₈)cycloalkenyl, optionally substituted(C₆-C₁₀)aryl, optionally substituted (C₁-C₁₀)heteroaryl, optionallysubstituted (C₂-C₁₀)heterocyclyl or -J-L-M-Q; wherein: J is a bond,—C(O)—, optionally substituted (C₁-C₆)alkylene, optionally substituted(C₂-C₆)alkenylene, optionally substituted (C₂-C₆)alkynylene, optionallysubstituted (C₃-C₁₂)cycloalkylene, optionally substituted(C₂-C₆)heterocyclylene, —C(O)N(R^(a))—R^(e)—, —N(R^(a))C(O)—R^(e)—,—O—R^(e)—, —N(R^(a))—R^(e)—, —S—R^(e)—, —S(O)₂—R^(e)—, —S(O)R^(e)—,—C(O—R^(a))(R^(b))—R^(e)—, —S(O)₂N(R^(a))—R^(e)—, —N(R^(a))S(O)₂—R^(e)—or —N(R^(a))C(O)N(R^(b))—R^(e)—; L is a bond, an optionally substituted(C₁-C₈)alkylene, optionally substituted bridged (C₅-C₁₂)cycloalkylene,optionally substituted (C₃-C₁₀)cycloalkylene, optionally substitutedbridged (C₅-C₁₀)cycloalkenylene, optionally substituted(C₃-C₁₀)cycloalkenylene, optionally substituted (C₆-C₁₀)arylene,optionally substituted (C₁-C₁₀)heteroarylene, optionally substitutedbridged (C₂-C₁₀)heterocyclylene or an optionally substituted(C₂-C₁₀)heterocyclylene; M is a bond, —R^(e)—, —R^(e)—C(O)—R^(e)—,—R^(e)—C(O)C(O)—R^(e)—, —R^(e)—C(O)O—R^(e)—, —R^(e)—OC(O)—R^(e),—R^(e)—C(O)C(O)N(R^(a))—R^(e)—, —R^(e)—N(R^(a))—C(O)C(O)—R^(e)—,—R^(e)—O—R^(e)—, —R^(e)— S(O)₂—R^(e)—, —R^(e)—S(O)—R^(e)—,—R^(e)—S—R^(e)—, —R^(e)—N(R^(a))—R^(e)—, —R^(e)—N(R^(a))C(O)—R^(e)—,—R^(e)—C(O)N(R^(a))R^(e)—, —R^(e)—OC(O)N(R^(a))—R^(e)—,—R^(e)—N(R^(a))C(O)OR^(e)—, —R^(e)—N(R^(a))C(O)N(R^(b))—R^(e)—,—R^(e)—N(R^(a))S(O)₂—R^(e)—, or —R^(e)—S(O)₂N(R^(a))—R^(e)—; or M is

where in all cases, M is linked to either a carbon or a nitrogen atom inL; Q is hydrogen, deuterium, —N(R^(a))(R^(b)), halogen, —OR^(a),—SR^(a), —S(O)R^(a), —S(O)₂R^(a), —NO₂, —C(O)OR^(a), —CN,—C(O)N(R^(a))(R^(b)), —N(R^(a))C(O)R^(b), —N(R^(a))C(O)OR^(b),—N(R^(a))C(O)N(R^(b))₂, —C(O—R^(a))(R^(b))₂, —C(O)R^(a), —CF₃, —OCF₃,—N(R^(a))S(O)₂R^(b), —S(O)₂N(R^(a))(R^(b)), —S(O)₂N(R^(a))C(O)R^(b), anoptionally substituted (C₁-C₆)alkyl, an optionally substituted(C₂-C₆)alkenyl, an optionally substituted (C₂-C₆)alkynyl, an optionallysubstituted (C₃-C₁₀)cycloalkyl, an optionally substituted(C₁-C₁₀)heteroaryl, an optionally substituted (C₁-C₁₀) heterocyclyl, anoptionally substituted (C₆-C₁₀)aryl; wherein in a moiety containing—N(R^(a))(R^(b)), the nitrogen, R^(a) and R^(b) may form a ring suchthat —N(R^(a))(R^(b)) represents an optionally substituted(C₂-C₁₀)heterocyclyl or an optionally substituted (C₁-C₁₀) heteroaryllinked through a nitrogen; R^(a) and R^(b) are each independentlyhydrogen, deuterium, CN, an optionally substituted (C₁-C₁₀)alkyl, anoptionally substituted (C₂-C₁₀)alkenyl, an optionally substituted(C₂-C₁₀)alkynyl, an optionally substituted(C₁-C₁₀)alkyl-O—(C₁-C₁₀)alkyl, an optionally substituted(C₃-C₁₀)cycloalkyl, an optionally substituted (C₆-C₁₀)aryl, anoptionally substituted (C₁-C₁₀)heteroaryl, an optionally substituted(C₁-C₁₀)heterocyclyl, an optionally substituted—(C₁-C₆)alkylene-(C₃-C₁₀)cycloalkyl, an optionally substituted—(C₁-C₆)alkylene-(C₆-C₁₀)aryl, an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heteroaryl, or an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heterocyclyl; and R^(e) for each occurrence isindependently a bond, an optionally substituted (C₁-C₁₀)alkylene, anoptionally substituted (C₂-C₁₀)alkenylene, an optionally substituted(C₂-C₁₀)alkynylene, an optionally substituted—(C₁-C₁₀)alkylene-O—(C₁-C₁₀)alkylene group, an optionally substituted(C₃-C₁₀)cycloalkylene, an optionally substituted (C₆-C₁₀)arylene, anoptionally substituted (C₁-C₁₀)heteroarylene, or an optionallysubstituted (C₁-C₁₀)heterocyclylene; provided that when T is N, U isCR⁴, X is NR³ and Y is C, R⁴ is not OH; provided that when T is N, U isCR⁴, X is NR³ and Y is C, R¹ is H; provided that when the compound is

R³ is defined as above and R⁶ is not linked to the pyrazole ring by anitrogen or oxygen atom; and provided that when the compound is

when R³ is H, CH₃ or C(O)OH then R⁴ is not H, —C(O)OCH₂CH₃,—C(O)NH-optionally substituted phenyl, —NHC(O)-optionally substitutedphenyl or S(O)₂-phenyl.
 2. The compound of claim 1 wherein R³ is-A-D-E-G and A is a bond, optionally substituted (C₁-C₆)alkylene,optionally substituted (C₃-C₁₂)cycloalkylene or optionally substituted(C₂-C₆)heterocyclylene.
 3. The compound of claim 1 wherein R³ is-A-D-E-G and D is an optionally substituted (C₁-C₈)alkylene, optionallysubstituted (C₃-C₁₀)cycloalkylene, optionally substituted bridged(C₅-C₁₀)cycloalkenylene, optionally substituted (C₃-C₁₀)bridgedheterocyclylene or optionally substituted (C₂-C₁₀)heterocyclylene. 4.The compound of claim 3 wherein D is optionally substituted(C₁-C₆)alkylene, optionally substituted (C₃-C₆)cycloalkylene, optionallysubstituted bicyclo[2.2.2]octany-1-yl, optionally substituted2,5-diazabicyclo[2.2.1]heptane, optionally substituted2,6-diazabicyclo[3.2.1]octane, optionally substitutedoctahydropyrrolo[3,4-c]pyrrole, optionally substitutedoctahydropyrrolo[3,2-b]pyridine, optionally substituted 1,4-diazepane,optionally substituted cubane, optionally substituted1,4-dioxane-spiro[4.4]nonane, optionally substituted2,5-diazaspiro[3.5]nonane, optionally substituted piperidine, optionallysubstituted piperazine, optionally substituted pyrrolidine, optionallysubstituted tetrahydrofuran or optionally substituted tetrahydropyran.5. The compound of claim 1 wherein R³ is -A-D-E-G and E is a bond,—R^(e)—, —R^(e)—C(O)—R^(e)—, —R^(e)—O—R^(e)—, —R^(e)—S(O)₂—R^(e)—,—R^(e)—N(R^(a))—R^(e)—, ═N—R^(e)—. —R^(e)—N(R^(a))C(O)—R^(e)—,—R^(e)—N(R^(a))C(O)O—R^(e)—, —R^(e)—N(R^(a))C(O)N(R^(b))—R^(e)—,—R^(e)C(O)N(R^(a))R^(e)—, —R^(e)—N(R^(a))S(O)₂—R^(e)—,—R^(e)—S(O)₂N(R^(a))—R^(e)—, —R^(e)—N(R^(a))S(O)₂N(R^(a))—R^(e)—,—R^(e)—OC(O)N(R^(a))—R^(e), —R^(e)—C(O)O—R^(e), —R^(e)—OC(O)—R^(e); or

wherein R^(a) for each occurrence is independently hydrogen, CN, anoptionally substituted (C₁-C₁₀)alkyl or an optionally substituted—(C₁-C₆)alkylene-(C₃-C₁₀)cycloalkyl; and R^(e) for each occurrence isindependently a bond, an optionally substituted (C₁-C₁₀)alkylene, anoptionally substituted (C₃-C₁₀)cycloalkylene, an optionally substituted(C₆-C₁₀)arylene, an optionally substituted (C₁-C₁₀)heteroarylene, or anoptionally substituted (C₁-C₁₀)heterocyclylene.
 6. The compound of claim1 wherein R³ is -A-D-E-G and G is hydrogen, deuterium, —N(R^(a))(R^(b)),halogen, —OR^(a), —S(O)₂R^(a), —CN, —C(O)N(R^(a))(R^(b)),—N(R^(a))C(O)R^(b), —CF₃, —S(O)₂N(R^(a))(R^(b)), an optionallysubstituted —(C₁-C₆)alkyl, an optionally substituted—(C₃-C₁₀)cycloalkyl, an optionally substituted —(C₁-C₁₀)heteroaryl, anoptionally substituted —(C₁-C₁₀) heterocyclyl, or an optionallysubstituted —(C₆-C₁₀)aryl; wherein in a moiety containing—N(R^(a))(R^(b)), the nitrogen, R^(a) and R^(b) may form a ring suchthat —N(R^(a))(R^(b)) represents an optionally substituted(C₂-C₁₀)heterocyclyl or an optionally substituted (C₁-C₁₀) heteroaryllinked through a nitrogen; R^(a) is independently hydrogen, CN, anoptionally substituted (C₁-C₁₀)alkyl, an optionally substituted(C₃-C₁₀)cycloalkyl, or an optionally substituted (C₆-C₁₀)aryl.
 7. Thecompound of claim 6 wherein G is hydrogen, deuterium, —N(R^(a))(R^(b)),halogen, —OR^(a), —S(O)₂R^(a), —CN, —C(O)N(R^(a))(R^(b)),—N(R^(a))C(O)R^(b), —CF₃, —S(O)₂N(R^(a))(R^(b)), an optionallysubstituted —(C₁-C₄)alkyl, an optionally substituted —(C₃-C₆)cycloalkyl,optionally substituted azepanyl, optionally substituted azetidinyl,optionally substituted benzo[d]isoxazolyl, optionally substituted4,5-dihydroisoxazolyl, optionally substituted isothiazolidinyl,optionally substituted isothiazolyl, optionally substituted isoxazolyl,optionally substituted morpholinyl, optionally substituted oxadiazolyl,optionally substituted oxazolyl, optionally substituted oxetanyl,optionally substitute phenyl, optionally substituted piperazinyl,optionally substituted piperidinyl, optionally substituted pyrazinyl,optionally substituted pyrazolyl, optionally substituted pyridazinyl,optionally substituted pyridinyl, optionally substituted pyrimidinyl,optionally substituted pyrrolidinyl, optionally substituted pyrrolyl,optionally substituted tetrahydrofuranyl, optionally substitutedtetrahydropyranyl, optionally substituted tetrahydrothiopyranyl,optionally substituted thienyl, optionally substituted thiomorpholinyl,optionally substituted 1,1-dioxo-thiomorpholinyl, optionally substitutedthiazolyl or optionally substituted triazolyl.
 8. The compound of claim1 wherein R³ is hydrogen, optionally substituted (C₁-C₈)alkyl,optionally substituted (C₃-C₁₀)cycloalkyl, or optionally substituted(C₂-C₁₀)heterocyclyl.
 9. The compound of claim 1 wherein R⁶ is J-L-M-Qand J is a bond, optionally substituted (C₁-C₆)alkylene, or anoptionally substituted (C₂-C₆)alkenylene.
 10. The compound of claim 1wherein R⁶ is J-L-M-Q and L is a bond, or an optionally substituted(C₁-C₈)alkylene.
 11. The compound of claim 1 wherein R⁶ is J-L-M-Q and Mis a bond, —R^(e)—, —R^(e)—C(O)—R^(e)—, —R^(e)—O—R^(e)—,—R^(e)—S(O)₂—R^(e)—, —R^(e)—S(O)—R^(e)—, —R^(e)—S—R^(e)—,—R^(e)—N(R^(a))—R^(e)—, —R^(e)—N(R^(a))C(O)—R^(e)—,—R^(e)—C(O)N(R^(a))R^(e)—, —R^(e)—N(R^(a))C(O)N(R^(b))—R^(e)—,—R^(e)—N(R^(a))S(O)₂—R^(e)—, or —R^(e)—S(O)₂N(R^(a))—R^(e)—; where inall cases, M is linked to either a carbon or a nitrogen atom in L. 12.The compound of claim 1 wherein R⁶ is J-L-M-Q and Q is hydrogen,deuterium, —N(R^(a))(R^(b)), halogen, —OR^(a), —SR^(a), —S(O)R^(a),—S(O)₂R^(a), —NO₂, —C(O)OR^(a), —CN, —C(O)N(R^(a))(R^(b)),—N(R^(a))C(O)R^(b), —N(R^(a))C(O)OR^(b), —N(R^(a))C(O)N(R^(b))₂,—C(O—R^(a))(R^(b))₂, —C(O)R^(a), —CF₃, —OCF₃, —N(R^(a))S(O)₂R^(b),—S(O)₂N(R^(a))(R^(b)), —S(O)₂N(R^(a))C(O)R^(b), an optionallysubstituted (C₁-C₆)alkyl, an optionally substituted (C₃-C₁₀)cycloalkyl,an optionally substituted (C₁-C₁₀)heteroaryl, an optionally substituted(C₁-C₁₀) heterocyclyl, an optionally substituted (C₆-C₁₀)aryl; whereinin a moiety containing —N(R^(a))(R^(b)), the nitrogen, R^(a) and R^(b)may form a ring such that —N(R^(a))(R^(b)) represents an optionallysubstituted (C₂-C₁₀)heterocyclyl or an optionally substituted (C₁-C₁₀)heteroaryl linked through a nitrogen; R^(a) and R^(b) are eachindependently hydrogen, deuterium, an optionally substituted(C₁-C₆)alkyl, an optionally substituted (C₂-C₁₀)alkenyl, an optionallysubstituted (C₃-C₆)cycloalkyl, an optionally substituted (C₆-C₁₀)aryl,an optionally substituted (C₁-C₁₀)heteroaryl, or an optionallysubstituted (C₁-C₁₀)heterocyclyl.
 13. The compound of claim 1 wherein Tis N, U is N, X is CR³ and Y is N and forms a compound of Formula (Ia)


14. The compound of claim 1 wherein T is CR⁶, U is N, X is CR³ and Y isN and forms a compound of Formula (Ib)


15. The compound of claim 1 wherein T is N, U is CR⁴, X is CR³ and Y isN and forms a compound of Formula (Ic)


16. The compound of claim 1 wherein T is CR⁶, U is CR⁴, X is CR³ and Yis N and forms a compound of Formula (Id)


17. The compound of claim 1 wherein T is CR⁶, U is N, X is NR³ and Y isC and forms a compound of Formula (Ie)


18. The compound of claim 1 wherein T is O, U is N, X is CR³ and Y is Cand forms a compound of Formula (If)


19. The compound of claim 1 wherein T is NR⁶, U is N, X is CR³ and Y isC and forms a compound of formula (Ig)


20. The compound of claim 1 wherein T is CR⁶, U is CR⁴, X is NR³ and Yis C and forms a compound of formula (Ih)


21. The compound of claim 1 wherein T is S, U is N, X is CR³ and Y is Cand forms a compound of Formula (Ii)


22. The compound of claim 1 wherein T is N, U is CR⁴, X is NR³ and Y isC and forms a compound of formula (Ij)


23. The compound of claim 1 wherein T is N, U is N, X is NR³ and Y is Cand forms a compound of Formula (Ik)


24. A compound of Formula (II) wherein the compound is

pharmaceutically acceptable salts, pro-drugs, biologically activemetabolites, stereoisomers and isomers thereof wherein R¹, and R² areindependently hydrogen, deuterium, —N(R^(a))(R^(b)), halogen, —OR^(a),—SR^(a), —S(O)R^(a), —S(O)₂R^(a), —NO₂, —C(O)OR^(a), —CN,—C(O)N(R^(a))(R^(b)), —N(R^(a))C(O)(R^(b)), —C(O)R^(a),—C(OH)R^(a)R^(b), —N(R^(a))S(O)₂—R^(b), —S(O)₂N(R^(a))(R^(b)), —CF₃,—OCF₃, optionally substituted (C₁-C₆)alkyl, optionally substituted(C₂-C₆)alkenyl, optionally substituted (C₂-C₆)alkynyl, optionallysubstituted (C₃-C₁₀)cycloalkyl, optionally substituted(C₁-C₁₀)heteroaryl, optionally substituted (C₁-C₁₀) heterocyclyl, oroptionally substituted (C₆-C₁₀)aryl; wherein in a moiety containing—N(R^(a))(R^(b)), the nitrogen, R^(a) and R^(b) may form a ring suchthat —N(R^(a))(R^(b)) represents an optionally substituted(C₂-C₁₀)heterocyclyl or optionally substituted (C₁-C₁₀)heteroaryl linkedthrough a nitrogen; R³ is hydrogen, an optionally substituted bridged(C₅-C₁₂)cycloalkyl, optionally substituted bridged (C₂-C₁₀)heterocyclyl,optionally substituted (C₁-C₈)alkyl, optionally substituted(C₃-C₁₀)cycloalkyl, optionally substituted (C₃-C₈)cycloalkenyl,optionally substituted (C₆-C₁₀)aryl, optionally substituted(C₁-C₁₀)heteroaryl, optionally substituted (C₂-C₁₀)heterocyclyl; or R³is -A-D-E-G, wherein: A is a bond, —C(O)—, optionally substituted(C₁-C₆)alkylene, optionally substituted (C₂-C₆)alkenylene, optionallysubstituted (C₂-C₆)alkynylene, optionally substituted(C₃-C₁₂)cycloalkylene, optionally substituted (C₂-C₆)heterocyclylene,—C(O)N(R^(a))—R^(e)—, —N(R^(a))C(O)—R^(e)—, —O—R^(e)—, —N(R^(a))—R^(e)—,—S—R^(e)—, —S(O)₂—R^(e)—, —S(O)R^(e)—, —C(O—R^(a))(R^(b))—R^(e)—,—S(O)₂N(R^(a))—R^(e)—, —N(R^(a))S(O)₂—R^(e)— or—N(R^(a))C(O)N(R^(b))—R^(e)—; D is an optionally substituted(C₁-C₈)alkylene, optionally substituted bridged (C₅-C₁₂)cycloalkylene,optionally substituted (C₃-C₁₀)cycloalkylene, optionally substitutedbridged (C₅-C₁₀)cycloalkenylene, optionally substituted(C₃-C₁₀)cycloalkenylene, optionally substituted (C₆-C₁₀)arylene,optionally substituted (C₁-C₁₀)heteroarylene, optionally substitutedbridged (C₂-C₁₀)heterocyclylene or an optionally substituted(C₂-C₁₀)heterocyclylene; E is a bond, —R^(e)—, —R^(e)—C(═NCN)—R^(e)—,—R^(e)—C(O)—R^(e)—, —R^(e)—C(O)C(O)—R^(e)—, —R^(e)—C(O)O—R^(e)—,—R^(e)—C(O)C(O)N(R^(a))—R^(e)—, —R^(e)—N(R^(a))—C(O)C(O)—R^(e)—,—R^(e)—O—R^(e)—, —R^(e)—S(O)₂—R^(e)—, —R^(e)—S(O)—R^(e)—,—R^(e)—S—R^(e)—, —R^(e)—N(R^(a))—R^(e)—, ═N—R^(e)—,—R^(e)—N(R^(a))C(O)—R^(e)—, —R^(e)C(O)N(R^(a))R^(e)—,—R^(e)—OC(O)N(R^(a))—R^(e)—, —R^(e)—N(R^(a))C(O)OR^(e)—,—R^(e)—OC(O)—R^(e), —R^(e)—OC(O)—O—R^(e),—R^(e)—N(R^(a))C(O)N(R^(b))—R^(e)—, —R^(e)—N(R^(a))S(O)₂—R^(e)—,—R^(e)—S(O)₂N(R^(a))—R^(e)—, or —R^(e)—N(R^(a))S(O)₂N(R^(a))—R^(e)—; orE is

where in all cases, E is linked to either a carbon or a nitrogen atom inD; G is hydrogen, deuterium, —N(R^(a))(R^(b)), halogen, —OR^(a),—SR^(a), —S(O)R^(a), —S(O)₂R^(a), —NO₂, —C(O)OR^(a), —CN,—C(O)N(R^(a))(R^(b)), —N(R^(a))C(O)R^(b), —N(R^(a))C(O)OR^(b),—OC(O)N(R^(a)), —N(R^(a))C(O)N(R^(b))₂, —C(O—R^(a))(R^(b))₂, —C(O)R^(a),—CF₃, —OCF₃, —N(R^(a))S(O)₂R^(b), —S(O)₂N(R^(a))(R^(b)),—S(O)₂N(R^(a))C(O)R^(b), an optionally substituted —(C₁-C₆)alkyl, anoptionally substituted —(C₂-C₆)alkenyl, an optionally substituted—(C₂-C₆)alkynyl, an optionally substituted —(C₃-C₁₀)cycloalkyl, anoptionally substituted —(C₁-C₁₀)heteroaryl, an optionally substituted—(C₁-C₁₀) heterocyclyl, an optionally substituted —(C₆-C₁₀)aryl; whereinin a moiety containing —N(R^(a))(R^(b)), the nitrogen, R^(a) and R^(b)may form a ring such that —N(R^(a))(R^(b)) represents an optionallysubstituted (C₂-C₁₀)heterocyclyl or an optionally substituted (C₁-C₁₀)heteroaryl linked through a nitrogen; R^(a) and R^(b) are eachindependently hydrogen, deuterium, CN, an optionally substituted(C₁-C₁₀)alkyl, an optionally substituted (C₂-C₁₀)alkenyl, an optionallysubstituted (C₂-C₁₀)alkynyl, an optionally substituted(C₁-C₁₀)alkyl-O—(C₁-C₁₀)alkyl, an optionally substituted(C₃-C₁₀)cycloalkyl, an optionally substituted (C₆-C₁₀)aryl, anoptionally substituted (C₁-C₁₀)heteroaryl, an optionally substituted(C₁-C₁₀)heterocyclyl, an optionally substituted—(C₁-C₆)alkylene-(C₃-C₁₀)cycloalkyl, an optionally substituted—(C₁-C₆)alkylene-(C₆-C₁₀)aryl, an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heteroaryl, or an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heterocyclyl; and R^(e) for each occurrence isindependently a bond, an optionally substituted (C₁-C₁₀)alkylene, anoptionally substituted (C₂-C₁₀)alkenylene, an optionally substituted(C₂-C₁₀)alkynylene, an optionally substituted—(C₁-C₁₀)alkylene-O—(C₁-C₁₀)alkylene group, an optionally substituted(C₃-C₁₀)cycloalkylene, an optionally substituted (C₆-C₁₀)arylene, anoptionally substituted (C₁-C₁₀)heteroarylene, or an optionallysubstituted (C₁-C₁₀)heterocyclylene.
 25. A pharmaceutical compositioncomprising a compound of Formula (I) as defined in claim 1 or Formula(II) as defined in claim 24

a pharmaceutically acceptable carrier and excipient and a secondtherapeutic agent selected from the group consisting of cytokinesuppressive anti-inflammatory drugs, antibodies to or antagonists ofother human cytokines or growth factors, IL-1, IL-2, IL-3, IL-4, IL-5,IL-6, IL-7, IL-8, IL-12, IL-15, IL-16, IL-21, IL-23, interferons,EMAP-II, GM-CSF, FGF, PDGF, CTLA or their ligands including CD154,HUMIRA™, REMICADE™, SIMPONI™ (golimumab), CIMZIA™, ACTEMRA™, CDP 571,soluble p55 or p75 TNF receptors, ENBREL™, Lenercept, TNFα convertingenzyme inhibitors, IL-1 inhibitors, Interleukin 11, IL-18 antagonists,IL-12 antagonists, IL-12 antibodies, soluble IL-12 receptors, IL-12binding proteins, non-depleting anti-CD4 inhibitors FK506, rapamycin,mycophenolate mofetil, leflunomide, NSAIDs, ibuprofen, corticosteroids,phosphodiesterase inhibitors, adensosine agonists, antithromboticagents, complement inhibitors, adrenergic agents, IL-1β convertingenzyme inhibitors, T-cell signalling kinase inhibitors,metalloproteinase inhibitors, sulfasalazine, 6-mercaptopurines,derivatives p75TNFRIgG, sIL-1RI, sIL-1RII, sIL-6R, celecoxib,hydroxychloroquine sulfate, rofecoxib, infliximab, naproxen, valdecoxib,sulfasalazine, meloxicam, acetate, gold sodium thiomalate, aspirin,triamcinolone acetonide, propoxyphene napsylate/apap, folate,nabumetone, diclofenac, piroxicam, etodolac, diclofenac sodium,oxaprozin, oxycodone HCl, hydrocodone bitartrate/apap, diclofenacsodium/misoprostol, fentanyl, anakinra, tramadol HCl, salsalate,sulindac, cyanocobalamin/fa/pyridoxine, acetaminophen, alendronatesodium, morphine sulfate, lidocaine hydrochloride, indomethacin,glucosamine sulf/chondroitin, amitriptyline HCl, sulfadiazine, oxycodoneHCl/acetaminophen, olopatadine HCl misoprostol, naproxen sodium,omeprazole, cyclophosphamide, rituximab, IL-1 TRAP, MRA, CTLA4-IG, IL-18BP, anti-IL-12, anti-IL15, VX-740, Roflumilast, IC-485, CDC-801, S1P1agonists, FTY720, PKC family inhibitors, Ruboxistaurin, AEB-071,Mesopram, methotrexate, leflunomide, corticosteroids, budenoside,dexamethasone, sulfasalazine, 5-aminosalicylic acid, olsalazine, IL-1βconverting enzyme inhibitors, IL-1ra, T cell signaling inhibitors,tyrosine kinase inhibitors, 6-mercaptopurines, IL-11, mesalamine,prednisone, azathioprine, mercaptopurine, infliximab, methylprednisolonesodium succinate, diphenoxylate/atrop sulfate, loperamide hydrochloride,omeprazole, folate, ciprofloxacin/dextrose-water, hydrocodone,bitartrate/apap, tetracycline hydrochloride, fluocinonide,metronidazole, thimerosal/boric acid, cholestyramine/sucrose,ciprofloxacin hydrochloride, hyoscyamine sulfate, meperidinehydrochloride, midazolam hydrochloride, oxycodone HCl/acetaminophen,promethazine hydrochloride, sodium phosphate,sulfamethoxazole/trimethoprim, polycarbophil, propoxyphene napsylate,hydrocortisone, multivitamins, balsalazide disodium, codeinephosphate/apap, colesevelam HCl, cyanocobalamin, folic acid,levofloxacin, natalizumab, interferon-gamma, methylprednisolone,azathioprine, cyclophosphamide, cyclosporine, methotrexate,4-aminopyridine, tizanidine, interferon-β1a, AVONEX®, interferon-β1b,BETASERON®, interferon α-n3, interferon-α, interferon β1A-IF,Peginterferon α 2b, Copolymer 1, COPAXONE®, hyperbaric oxygen,intravenous immunoglobulin, cladribine, cyclosporine, FK506,mycophenolate mofetil, leflunomide, NSAIDs, corticosteroids,prednisolone, phosphodiesterase inhibitors, adensosine agonists,antithrombotic agents, complement inhibitors, adrenergic agents,antiinflammatory cytokines, interferon-β, IFNβ1a, IFNβ1b, copaxone,corticosteroids, caspase inhibitors, inhibitors of caspase-1, antibodiesto CD40 ligand and CD80, alemtuzumab, dronabinol, daclizumab,mitoxantrone, xaliproden hydrochloride, fampridine, glatiramer acetate,natalizumab, sinnabidol, α-immunokine NNSO3, ABR-215062, AnergiX.MS,chemokine receptor antagonists, BBR-2778, calagualine, CPI-1189,liposome encapsulated mitoxantrone, THC.CBD, cannabinoid agonists,MBP-8298, mesopram, MNA-715, anti-IL-6 receptor antibody, neurovax,pirfenidone allotrap 1258 (RDP-1258), sTNF-R1, talampanel,teriflunomide, TGF-beta2, tiplimotide, VLA-4 antagonists, interferongamma antagonists, IL-4 agonists, diclofenac, misoprostol, naproxen,meloxicam, indomethacin, diclofenac, methotrexate, azathioprine,minocyclin, prednisone, etanercept, rofecoxib, sulfasalazine, naproxen,leflunomide, methylprednisolone acetate, indomethacin,hydroxychloroquine sulfate, prednisone, sulindac, betamethasone dipropaugmented, infliximab, methotrexate, folate, triamcinolone acetonide,diclofenac, dimethylsulfoxide, piroxicam, diclofenac sodium, ketoprofen,meloxicam, methylprednisolone, nabumetone, tolmetin sodium,calcipotriene, cyclosporine, diclofenac sodium/misoprostol,fluocinonide, glucosamine sulfate, gold sodium thiomalate, hydrocodonebitartrate/apap, risedronate sodium, sulfadiazine, thioguanine,valdecoxib, alefacept, and efalizumab, diclofenac, naproxen, ibuprofen,piroxicam, indomethacin, COX2 inhibitors, rofecoxib, valdecoxib,hydroxychloroquine, steroids, prednisolone, budenoside, dexamethasone,cytotoxics, azathioprine, cyclophosphamide, mycophenolate mofetil,inhibitors of PDE4, purine synthesis inhibitor, sulfasalazine,5-aminosalicylic acid, olsalazine, Imuran®, CTLA-4-IgG, anti-B7 familyantibodies, anti-PD-1 family antibodies, anti-cytokine antibodies,fonotolizumab, anti-IFNg antibody, anti-receptor receptor antibodies,anti-IL-6 receptor antibody, antibodies to B-cell surface molecules, LJP394, Rituximab, anti-CD20 antibody and lymphostat-B.